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

Multidrug Resistant Tuberculosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02120638
• Other study ID #: KY2013-260
• Secondary ID: 2013ZX10003008-0
• Status: Recruiting
• Phase: Phase 3
• First received: April 21, 2014
• Last updated: April 21, 2014
• Start date: April 2014
• Est. completion date: April 2016

Study information

• Verified date: April 2014
• Source: Huashan Hospital
• Contact: Wenhong Zhang, PhD,MD
• Phone: +86 21 52889999
• Email: zhangwenhong[@]fudan.edu.cn
• Is FDA regulated: No
• Health authority: China: Ministry of Science and Technology
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: April 2016
• Est. primary completion date: April 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Disease Susceptibility
• Multidrug Resistant Tuberculosis
• Tuberculosis
• Tuberculosis, Multidrug-Resistant

Intervention

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.
• 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.

Locations

Country	Name	City	State
China	Chongqing Pulmonary Hospital	Chongqing	Chongqing
China	Hangzhou Red Cross Hospital	Hangzhou	Zhejiang
China	The Affiliated Hospital of Hangzhou Normal University	Hangzhou	Zhejiang
China	The Affiliated Hospital of Luzhou Medical College	Huzhou	Zhejiang
China	The Fifth People's Hospital of Suzhou	Suzhou	Jiangsu
China	Wenling No.1 People's Hospital	Taizhou	Zhejiang
China	Xinjiang Chest Hospital	Urumqi	Xinjiang
China	Ruian People's Hospital	Wenzhou	Zhejiang
China	The Fifth People's Hospital of Wuxi	Wuxi	Jiangsu
China	The Sixth People's Hospital of Zhengzhou	Zhengzhou	Henan
China	Zhuji People's Hospital of Zhejiang Province	Zhuji	Zhejiang

Sponsors (1)

Lead Sponsor	Collaborator
Huashan Hospital

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Median Time to Sputum Culture Conversion		24 months	No
Secondary	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.	24 months	No