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NGS-Guided(G) Regimens(R) of Anti-tuberculosis(A) Drugs for the Control(C) and Eradication(E) of MDR-TB (GRACE-TB)

Primary Purpose

Multidrug Resistant Tuberculosis

Status
Not yet recruiting
Phase
Not Applicable
Locations
China
Study Type
Interventional
Intervention
WHO-approved MDR-TB regimen
NGS-guided regimen: Regimen A
NGS-guided regimen: Regimen B
NGS-guided regimen: Regimen C
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, next generation sequencing, drug susceptibility test, precision treatment

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients who are diagnosed with active MDR-TB. MDR-TB is defined as resistance to the following two drugs: Isoniazid and Rifampicin.
  • 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:

  • 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 <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.

Sites / Locations

  • The Third People's Hospital of Shenzhen City
  • the First Affiliated Hospital of Harbin Medical University
  • The Sixth People's Hospital of Zhengzhou
  • The Fifth People's Hospital of Suzhou
  • The Affiliated Hospital of Southwest Medical University
  • Chest Hospitalof Xinjiang Uygur Autonomous Region of PRC
  • Zhuji City People's Hospital
  • Hangzhou Red Cross Hospital
  • Zhejiang Provincial Center for Disease Control and Prevention
  • The Second Hospital of Yinzhou of Ningbo
  • Enze Medical Center of Taizhou CIty
  • The Central Hospital of Wenzhou City

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Active Comparator

Arm Label

NGS-guided regimen: Regimen A

NGS-guided regimen: Regimen B

NGS-guided regimen: Regimen C

WHO-approved MDR-TB regimen

Arm Description

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

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

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.

6 months of pyrazinamide, amikacin,moxifloxacin, prothionamide , and cycloserine , followed by 18 months of pyrazinamide, moxifloxacin, prothionamide , and cycloserine

Outcomes

Primary Outcome Measures

Efficacy of NGS-guided treatment(the proportion of patients with a favorable efficacy outcome 18 months after the end of treatment)
to compare the proportion of patients with a favorable efficacy outcome between the NGS-guided group and conventional WHO-approved MDR-TB group

Secondary Outcome Measures

Efficacy of shorter course regimen for simple MDR-TB patients(the proportion of patients with a favorable efficacy outcome between regimen A and regimen B)
to assess whether the proportion of simple MDR-TB patients with a favorable efficacy outcome of Regimen A is not inferior to Regimen B
Safety(the proportion of patients who experience grade 3 or greater adverse events)
to compare the proportion of patients who experience grade 3 or greater adverse events (graded according to the Division of AIDS severity criteria for adverse events), during treatment or follow-up, on the experimental regimen when compared to the control regimen;
The Median Time to Sputum Culture Conversion
time from treatment initiation to the first of two consecutive negative sputum cultures without an intervening positive culture in liquid media between the NGS-guided group and conventional WHO-approved MDR-TB group;

Full Information

First Posted
June 26, 2018
Last Updated
July 19, 2018
Sponsor
Huashan Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT03604848
Brief Title
NGS-Guided(G) Regimens(R) of Anti-tuberculosis(A) Drugs for the Control(C) and Eradication(E) of MDR-TB
Acronym
GRACE-TB
Official Title
GRACE-TB:NGS-guided Regimens of Anti-tuberculosis Drugs for the Control and Eradication of MDR-TB
Study Type
Interventional

2. Study Status

Record Verification Date
July 2018
Overall Recruitment Status
Not yet recruiting
Study Start Date
August 5, 2018 (Anticipated)
Primary Completion Date
August 4, 2024 (Anticipated)
Study Completion Date
August 4, 2024 (Anticipated)

3. Sponsor/Collaborators

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Tuberculosis (TB) has been one of the top 10 causes of death worldwide from a single infectious agent, ranking above HIV/AIDS. Management and eradication of this disease is being hindered by the emergence of multidrug-resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB). Globally, there were estimated 10.4 million cases of TB and 490,000 cases of MDR-TB in 2016. China accounts for around 8.6% (0.895/10.4 million) of the global TB burden, ranking third in the top 3 countries (India, Indonesia, China) with the highest number of TB cases and ranking first with the largest number of MDR/ Rifampin-Resistant (RR)-TB cases. The treatment success rate for MDR-TB using the 18-24-month conventional World Health Organization (WHO) regimen was estimated to be about 54% worldwide and 41% for China in 2016, which remains unacceptably low. 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.
Detailed Description
The GRACE-TB study is a multi-center, open-label, randomized, controlled trial in patients with MDR-TB. This study will assess the feasibility and effects of individualized regimen for MDR-TB based on rapid molecular drug susceptibility tests(DSTs) of key second-line drugs through next generation sequencing (NGS) and try to improve the treatment outcome of MDR-TB. And the study will evaluate a shorter course regimen among patients who are proven to be sensitive to fluoroquinolones (FQs) or second-line injectable drugs(SLIDs) or pyrazinamide (PZA) through NGS. 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.

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, next generation sequencing, drug susceptibility test, precision treatment

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
488 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
NGS-guided regimen: Regimen A
Arm Type
Experimental
Arm Description
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
Arm Title
NGS-guided regimen: Regimen B
Arm Type
Experimental
Arm Description
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
Arm Title
NGS-guided regimen: Regimen C
Arm Type
Experimental
Arm Description
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.
Arm Title
WHO-approved MDR-TB regimen
Arm Type
Active Comparator
Arm Description
6 months of pyrazinamide, amikacin,moxifloxacin, prothionamide , and cycloserine , followed by 18 months of pyrazinamide, moxifloxacin, prothionamide , and cycloserine
Intervention Type
Drug
Intervention Name(s)
WHO-approved MDR-TB regimen
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
NGS-guided regimen: Regimen A
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
NGS-guided regimen: Regimen B
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
NGS-guided regimen: Regimen C
Intervention Description
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;
Primary Outcome Measure Information:
Title
Efficacy of NGS-guided treatment(the proportion of patients with a favorable efficacy outcome 18 months after the end of treatment)
Description
to compare the proportion of patients with a favorable efficacy outcome between the NGS-guided group and conventional WHO-approved MDR-TB group
Time Frame
18 months after the end of treatment
Secondary Outcome Measure Information:
Title
Efficacy of shorter course regimen for simple MDR-TB patients(the proportion of patients with a favorable efficacy outcome between regimen A and regimen B)
Description
to assess whether the proportion of simple MDR-TB patients with a favorable efficacy outcome of Regimen A is not inferior to Regimen B
Time Frame
18 months after the end of treatment
Title
Safety(the proportion of patients who experience grade 3 or greater adverse events)
Description
to compare the proportion of patients who experience grade 3 or greater adverse events (graded according to the Division of AIDS severity criteria for adverse events), during treatment or follow-up, on the experimental regimen when compared to the control regimen;
Time Frame
18 months after the end of treatment
Title
The Median Time to Sputum Culture Conversion
Description
time from treatment initiation to the first of two consecutive negative sputum cultures without an intervening positive culture in liquid media between the NGS-guided group and conventional WHO-approved MDR-TB group;
Time Frame
24 months after the start of treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients who are diagnosed with active MDR-TB. MDR-TB is defined as resistance to the following two drugs: Isoniazid and Rifampicin. 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: 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 <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.
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
First Name & Middle Initial & Last Name or Official Title & Degree
Feng Sun, MD
Phone
+86 21 52889999
Ext
7932
Email
aaronsf1125@126.com
Overall Study Officials:
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
The Third People's Hospital of Shenzhen City
City
Shenzhen
State/Province
Guangzhou
Country
China
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Guofang Deng
Email
lalaliy@sina.com
Facility Name
the First Affiliated Hospital of Harbin Medical University
City
Harbin
State/Province
Heilongjiang
Country
China
Facility Name
The Sixth People's Hospital of Zhengzhou
City
Zhengzhou
State/Province
Henan
Country
China
Facility Name
The Fifth People's Hospital of Suzhou
City
Suzhou
State/Province
Jiangsu
Country
China
Facility Name
The Affiliated Hospital of Southwest Medical University
City
Luzhou
State/Province
Sichuan
Country
China
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Fuli Huang
Email
flh905@aliyun.com
Facility Name
Chest Hospitalof Xinjiang Uygur Autonomous Region of PRC
City
Urumqi
State/Province
Xinjiang
Country
China
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Wenlong Guan
Email
18999918582@189.cn
Facility Name
Zhuji City People's Hospital
City
Zhuji
State/Province
Zhejaing
Country
China
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Heqing Huang
Email
zjganran@163.com
Facility Name
Hangzhou Red Cross Hospital
City
Hangzhou
State/Province
Zhejiang
Country
China
Facility Name
Zhejiang Provincial Center for Disease Control and Prevention
City
Hangzhou
State/Province
Zhejiang
Country
China
Facility Name
The Second Hospital of Yinzhou of Ningbo
City
Ningbo
State/Province
Zhejiang
ZIP/Postal Code
315040
Country
China
Facility Name
Enze Medical Center of Taizhou CIty
City
Taizhou
State/Province
Zhejiang
Country
China
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zebao He
Email
hezb@enzemed.com
Facility Name
The Central Hospital of Wenzhou City
City
Wenzhou
State/Province
Zhejiang
Country
China
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Xiangao Jiang
Email
shijichan@163.com

12. IPD Sharing Statement

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NGS-Guided(G) Regimens(R) of Anti-tuberculosis(A) Drugs for the Control(C) and Eradication(E) of MDR-TB

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