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

NCT03604848 | Unknown DMC

• 1 other identifier: KY2018-291
• Study Type: interventional
• Target: 488
• Locations: 1 country
• Sites: 12

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.

Conditions

Multidrug Resistant Tuberculosis

Keywords

Multidrug Resistant Tuberculosis; next generation sequencing; drug susceptibility test; precision treatment

Outcome Measures

Primary Outcomes (1)

• 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

  18 months after the end of treatment

Secondary Outcomes (3)

• 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)

  18 months after the end of treatment

• Safety(the proportion of patients who experience grade 3 or greater adverse events)

  18 months after the end of treatment

• The Median Time to Sputum Culture Conversion

  24 months after the start of treatment

Study Arms (4)

NGS-guided regimen: Regimen A

EXPERIMENTAL

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

Drug: NGS-guided regimen: Regimen A

NGS-guided regimen: Regimen B

EXPERIMENTAL

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

Drug: NGS-guided regimen: Regimen B

NGS-guided regimen: Regimen C

EXPERIMENTAL

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.

Drug: NGS-guided regimen: Regimen C

WHO-approved MDR-TB regimen

ACTIVE COMPARATOR

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

Drug: WHO-approved MDR-TB regimen

Interventions

WHO-approved MDR-TB regimen DRUG

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.

WHO-approved MDR-TB regimen

NGS-guided regimen: Regimen A DRUG

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

NGS-guided regimen: Regimen B DRUG

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

NGS-guided regimen: Regimen C DRUG

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;

NGS-guided regimen: Regimen C

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Huashan Hospital: lead

Study Sites (12)

The Third People's Hospital of Shenzhen City

Shenzhen, Guangzhou, China

Location

the First Affiliated Hospital of Harbin Medical University

Harbin, Heilongjiang, China

Location

The Sixth People's Hospital of Zhengzhou

Zhengzhou, Henan, China

Location

The Fifth People's Hospital of Suzhou

Suzhou, Jiangsu, China

Location

The Affiliated Hospital of Southwest Medical University

Luzhou, Sichuan, China

Location

Chest Hospitalof Xinjiang Uygur Autonomous Region of PRC

Ürümqi, Xinjiang, China

Location

Zhuji City People's Hospital

Zhuji, Zhejaing, China

Location

Hangzhou Red Cross Hospital

Hangzhou, Zhejiang, China

Location

Zhejiang Provincial Center for Disease Control and Prevention

Hangzhou, Zhejiang, China

Location

The Second Hospital of Yinzhou of Ningbo

Ningbo, Zhejiang, 315040, China

Location

Enze Medical Center of Taizhou CIty

Taizhou, Zhejiang, China

Location

The Central Hospital of Wenzhou City

Wenzhou, Zhejiang, China

Location

MeSH Terms

Conditions

Tuberculosis, Multidrug-Resistant

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Study Officials

• Wenhong Zhang, PhD,MD

  Huashan Hospital of Fudan University, Shanghai, China

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Wenhong Zhang, PhD,MD

CONTACT

+86 21 52889999; zhangwenhong@fudan.edu.cn

Feng Sun, MD

CONTACT

+86 21 52889999; aaronsf1125@126.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Division of Infectious Diseases

Study Record Dates

• First Submitted: June 26, 2018
• First Posted: July 30, 2018
• Study Start: August 5, 2018
• Primary Completion: August 4, 2024
• Study Completion: August 4, 2024
• Last Updated: July 30, 2018

Record last verified: 2018-07

Locations

CN (12)