NGS-Guided(G) Regimens(R) of Anti-tuberculosis(A) Drugs for the Control(C) and Eradication(E) of MDR-TB
NCT ID: NCT03604848
Last Updated: 2018-07-30
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
NA
488 participants
INTERVENTIONAL
2018-08-05
2024-08-04
Brief Summary
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The poor MDR-TB treatment success rates suggest that current drug regimens are suboptimal. In addition, they are costly with a high pill burden, as many drugs, with significant potential for adverse events, are given for a long duration. These factors also inhibit good treatment compliance with further negative impact on treatment outcomes. According to previous studies, treatment outcomes of MDR-TB could be affected by drug resistance of pivotal drugs in MDR-TB regimen, such as fluoroquinolones, second-line injectable agents and pyrazinamide. The available drug-resistance information could help physicians decide the proper regimens for MDR-TB patients, which may prevent the useless prescription and evitable adverse.
Therefore, the individualized regimen based on the resistance profile of the bacteria and patients' drug tolerance should be aimed for high-quality treatment for MDR-TB in the future. A precision individualized treatment approach based on the rapid molecular drug susceptibility tests of second line drugs may assist clinicians in making more suitable regimen and improve the treatment outcome of MDR-TB. Also, precision regimen offers the opportunity to improve treatment of drug-resistant tuberculosis through reduced toxicity while reducing the risk of resistance amplification and further transmission at a population level.
The purpose of this research is to assess the feasibility and effects of individualized regimen that is guided by rapid molecular drug susceptibility tests of key second-line drugs through next generation sequencing. Meanwhile, the study will evaluate a short course regimens of drugs among "simple MDR-TB" patients who are proven to be sensitive to fluoroquinolones ,injectable second-line drugs and pyrazinamide.
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Detailed Description
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A total of 488 participants with MDR-TB will be recruited and followed up until 18 months after the end of treatment. During randomization, eligible patients will be assigned in a 1:3 ratio to one of the following groups: a control group, which is treated with WHO-approved MDR-TB regimen, composed of 6 months of PZA, amikacin (Am) ,moxifloxacin (MFX), prothionamide (PTO), and Cycloserine (Cs), followed by 18 months of PZA, MFX, PTO and Cs; a NGS-guided group, which is treated with one individualized regimen that is guided by the drug susceptability test results of FQs/PZA/ SLIDs through NGS.
About 366 patients will be enrolled in the NGS-guided group. Based on the molecular DST results of FQs/PZA/ SLIDs , patients proven to be sensitive to PZA, FQs and SLIDs will be divided into to the "simple MDR-TB group" and those with resistant to at least one of FQs/PZA/ SLIDs will be divided into to "complicated MDR-TB group".
Patients in the "simple MDR-TB group" will be assigned randomly in a 1:1 ratio to one of the following daily regimen: a 9-month regimen(Regimen A) which consists of 4-month intensive therapy of PZA, Am, MFX,PTO, Cs, followed by 5-month consolidation therapy of PZA, MFX, PTO and Cs; a 12-month regimen(Regimen B) which consists of 6-month intensive therapy of PZA, Am, MFX,PTO, Cs, followed by 6-month consolidation therapy of PZA, MFX, PTO and Cs.
Patients in the "complicated MDR-TB group" will be treated a regimen (Regimen C) in which the resistant drug(s) will be replaced by the other WHO recommended drugs for MDR-TB such as linezolid, clofazimine or ethambutol based on the DST results. The duration of treatment in the "complicated MDR-TB group" is consistent with control group, with 6 months of intensive phase and 18 months of consolidation phase.
The primary objective is to compare the proportion of patients with a favorable efficacy between the NGS-guided group and the control group. The second objective is to assess whether the proportion of simple MDR-TB patients with a favorable efficacy outcome of Regimen A is not inferior to Regimen B. The participants will be followed up to 18 months after the end of the treatment. The data accrued to 18 months after the end of treatment will be used in primary and secondary analyses.
Safety evaluations performed are the routine lab tests, blood glucose, hearing, vital signs, electrocardiograph (ECG), reporting of adverse events, physical examinations and chest CT. Adverse events will be monitored and promptly managed during the whole treatment course.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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NGS-guided regimen: Regimen A
Regimen A: 9-month regimen for simple MDR-TB patients 4 months of pyrazinamide, amikacin ,moxifloxacin, prothionamide, and cycloserine , followed by 5months of pyrazinamide,moxifloxacin, prothionamide, and cycloserine
NGS-guided regimen: Regimen A
Pyrazinamide 33-50kg 1000-1750 mg daily, 51-70kg 1750-2000 daily, \>70kg 2000-2500mg daily; Amikacin 600mg daily ; Moxifloxacin 33-50kg 400 mg daily, 51-70kg 600mg daily, \>70kg 800mg daily; Prothionamide 33-50kg 500 mg daily, 51-70kg 750 daily, \>70kg 1000 mg daily ; Cycloserine 33-50kg 500 mg daily, 51-70kg 750 daily, \>70kg 1000 mg daily All treatment is taken daily.
NGS-guided regimen: Regimen B
Regimen B: 12-month simple MDR-TB regimen for simple MDR-TB patients 6 months of pyrazinamide, amikacin ,moxifloxacin, prothionamide, and cycloserine , followed by 6 months of pyrazinamide,moxifloxacin, prothionamide, and cycloserine
NGS-guided regimen: Regimen B
Pyrazinamide 33-50kg 1000-1750 mg daily, 51-70kg 1750-2000 daily, \>70kg 2000-2500mg daily; Amikacin 600mg daily ; Moxifloxacin 33-50kg 400 mg daily, 51-70kg 600mg daily, \>70kg 800mg daily; Prothionamide 33-50kg 500 mg daily, 51-70kg 750 daily, \>70kg 1000 mg daily ; Cycloserine 33-50kg 500 mg daily, 51-70kg 750 daily, \>70kg 1000 mg daily All treatment is taken daily.
NGS-guided regimen: Regimen C
Regimen C : for complicated MDR-TB patients In regimen C, the resistant drug(s) will be replaced by the other WHO recommended drugs for MDR-TB such as linezolid, clofazimine or ethambutol based on the drug susceptibility test results. The duration of treatment in the "complicated MDR-TB group" is consistent with control group, with 6 months of intensive phase and 18 months of consolidation phase.
NGS-guided regimen: Regimen C
Based on the drug susceptibility test results, the resistant drug(s) will be replaced by the other WHO recommended drugs for MDR-TB such as linezolid, clofazimine or ethambutol.
The dose of linezolid, clofazimine or ethambutol as follows:
Linezolid: 600 mg daily, clofazamine: 33-50kg 50 mg daily, 51-70kg 100 daily, \>70kg 100 mg daily; ethambutol: 33-50kg 800 mg daily, 51-70kg 800 daily, \>70kg 1200 mg daily;
WHO-approved MDR-TB regimen
6 months of pyrazinamide, amikacin,moxifloxacin, prothionamide , and cycloserine , followed by 18 months of pyrazinamide, moxifloxacin, prothionamide , and cycloserine
WHO-approved MDR-TB regimen
Pyrazinamide 33-50kg 1000-1750 mg daily, 51-70kg 1750-2000 daily, \>70kg 2000-2500mg daily; Amikacin 600mg daily ; Moxifloxacin 33-50kg 400 mg daily, 51-70kg 600mg daily, \>70kg 800mg daily; Prothionamide 33-50kg 500 mg daily, 51-70kg 750 daily, \>70kg 1000 mg daily ; Cycloserine 33-50kg 500 mg daily, 51-70kg 750 daily, \>70kg 1000 mg daily All treatment is taken daily.
Interventions
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WHO-approved MDR-TB regimen
Pyrazinamide 33-50kg 1000-1750 mg daily, 51-70kg 1750-2000 daily, \>70kg 2000-2500mg daily; Amikacin 600mg daily ; Moxifloxacin 33-50kg 400 mg daily, 51-70kg 600mg daily, \>70kg 800mg daily; Prothionamide 33-50kg 500 mg daily, 51-70kg 750 daily, \>70kg 1000 mg daily ; Cycloserine 33-50kg 500 mg daily, 51-70kg 750 daily, \>70kg 1000 mg daily All treatment is taken daily.
NGS-guided regimen: Regimen A
Pyrazinamide 33-50kg 1000-1750 mg daily, 51-70kg 1750-2000 daily, \>70kg 2000-2500mg daily; Amikacin 600mg daily ; Moxifloxacin 33-50kg 400 mg daily, 51-70kg 600mg daily, \>70kg 800mg daily; Prothionamide 33-50kg 500 mg daily, 51-70kg 750 daily, \>70kg 1000 mg daily ; Cycloserine 33-50kg 500 mg daily, 51-70kg 750 daily, \>70kg 1000 mg daily All treatment is taken daily.
NGS-guided regimen: Regimen B
Pyrazinamide 33-50kg 1000-1750 mg daily, 51-70kg 1750-2000 daily, \>70kg 2000-2500mg daily; Amikacin 600mg daily ; Moxifloxacin 33-50kg 400 mg daily, 51-70kg 600mg daily, \>70kg 800mg daily; Prothionamide 33-50kg 500 mg daily, 51-70kg 750 daily, \>70kg 1000 mg daily ; Cycloserine 33-50kg 500 mg daily, 51-70kg 750 daily, \>70kg 1000 mg daily All treatment is taken daily.
NGS-guided regimen: Regimen C
Based on the drug susceptibility test results, the resistant drug(s) will be replaced by the other WHO recommended drugs for MDR-TB such as linezolid, clofazimine or ethambutol.
The dose of linezolid, clofazimine or ethambutol as follows:
Linezolid: 600 mg daily, clofazamine: 33-50kg 50 mg daily, 51-70kg 100 daily, \>70kg 100 mg daily; ethambutol: 33-50kg 800 mg daily, 51-70kg 800 daily, \>70kg 1200 mg daily;
Eligibility Criteria
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Inclusion Criteria
* Patients who are smear positive and sputum culture positive for mycobacterium tuberculosis
* HIV negative.
* 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.
Exclusion Criteria
* 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 \<150x10\^9 / L, WBC \< 3x10\^9 / 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.
18 Years
70 Years
ALL
No
Sponsors
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Huashan Hospital
OTHER
Responsible Party
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Wen-hong Zhang
Director of Division of Infectious Diseases
Principal Investigators
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Wenhong Zhang, PhD,MD
Role: PRINCIPAL_INVESTIGATOR
Huashan Hospital of Fudan University, Shanghai, China
Locations
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The Third People's Hospital of Shenzhen City
Shenzhen, Guangzhou, China
the First Affiliated Hospital of Harbin Medical University
Harbin, Heilongjiang, China
The Sixth People's Hospital of Zhengzhou
Zhengzhou, Henan, China
The Fifth People's Hospital of Suzhou
Suzhou, Jiangsu, China
The Affiliated Hospital of Southwest Medical University
Luzhou, Sichuan, China
Chest Hospitalof Xinjiang Uygur Autonomous Region of PRC
Ürümqi, Xinjiang, China
Zhuji City People's Hospital
Zhuji, Zhejaing, China
Hangzhou Red Cross Hospital
Hangzhou, Zhejiang, China
Zhejiang Provincial Center for Disease Control and Prevention
Hangzhou, Zhejiang, China
The Second Hospital of Yinzhou of Ningbo
Ningbo, Zhejiang, China
Enze Medical Center of Taizhou CIty
Taizhou, Zhejiang, China
The Central Hospital of Wenzhou City
Wenzhou, Zhejiang, China
Countries
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Central Contacts
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Facility Contacts
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Other Identifiers
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KY2018-291
Identifier Type: -
Identifier Source: org_study_id
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