NCT03604848

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

GRACE-TB：NGS-guided Regimens of Anti-tuberculosis Drugs for the Control and Eradication of MDR-TB

• Status: Unknown
• Phase: N/A
• Study type: Interventional
• Enrollment: 488 (estimated)
• Sponsor: Huashan Hospital · Academic / Other
• Sex: All
• Age: 18 Years – 70 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Multidrug Resistant Tuberculosis

Interventions

Type	Name	Description
DRUG	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.
DRUG	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.
DRUG	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.
DRUG	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;

Timeline

• Start date: 2018-08-05
• Primary completion: 2024-08-04
• Completion: 2024-08-04
• First posted: 2018-07-30
• Last updated: 2018-07-30

Locations

12 sites across 1 country: China