International Research in Korea: Clinical Studies of Drug-Resistant Tuberculosis

韩国国际研究：耐药结核病的临床研究

• 批准号: 8946454
• 负责人: Clifton Barry
• 金额: $ 60.8万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8946454
• 关键词: Address; Adverse event; Aerobic; Affect; Aminoglycosides; Award; Basic Science; Biological Assay; Biological Markers; Biology; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Research; Clinical Trials; Collaborations; Conduct Clinical Trials; Cross-Sectional Studies; Detection; Development; Diabetes Mellitus; Diagnosis; Diagnostic tests; Diagnostics Research; Disease; Dose; Double-Blind Method; Drug Kinetics; Drug Resistant Tuberculosis; Drug resistance; Drug resistance in tuberculosis; Drug-sensitive; Enrollment; Evaluable Disease; Excision; Extreme drug resistant tuberculosis; Fluoroquinolones; Funding Mechanisms; Future; Genome; Goals; Grant; Health; Health Sciences; Image; Infection; Insurance; International; Investigation; Kanamycin Resistance; Korea; Koreans; Lesion; Linezolid; Liquid substance; Lung; Mass Spectrum Analysis; Medical center; Medicine; Methods; Metronidazole; Minimum Inhibitory Concentration measurement; Modeling; Molecular; Monitor; Moxifloxacin; Multicenter Studies; Multidrug-Resistant Tuberculosis; Multiple drug resistant Mycobacteria Tuberculosis; Mutation; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Natural History; Nitroimidazoles; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; PET/CT scan; Pathology; Patients; Penetration; Performance; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phase; Pilot Projects; Placebo Control; Placebos; Positron-Emission Tomography; Predisposition; Preventive; Protocols documentation; Province; Public Health; Publishing; Pulmonary Tuberculosis; Randomized; Refractory; Regimen; Relapse; Research; Research Personnel; Resistance; Resort; Retreatment; Rifampicin resistance; Risk; Risk Factors; Safety; Sensitivity and Specificity; Smoking; Social Welfare; South Africa; South Korea; Sputum; Stratification; Susceptibility Gene; Testing; Thoracic Radiography; Traumeel S; Treatment Protocols; Treatment outcome; Tuberculosis; Universities; University Hospitals; Work; advanced disease; arm; base; chemotherapy; clinically significant; college; drug distribution; experience; fitness; fluoroquinolone resistance; follow-up; genome sequencing; human disease; isoniazid; laboratory facility; lung volume; neurotoxic; next generation; novel; novel diagnostics; open label; prospective; response; success; treatment response; tuberculosis drugs; tuberculosis treatment; uptake

The project is a collaboration between the TRS/LCID/NIAID, Korean Ministry of Health & Welfare, Korea CDC, and Yonsei University College of Medicine in the Republic of Korea. These collaborators have worked together to establish the International Tuberculosis Research Center (ITRC) that manages both financial and scientific activities within the laboratory facilities, including a fully functional BSL3 laboratory facility. In addition, studies are being conducted in collaboration with Asan Medical Center, Samsung Medical Center, Pusan National University Hospital, and the National Medical Center, all located in Seoul. Specific protocol-driven investigations underway include: (1) NIAID 05-I-N069: A Natural History Study of MDR-TB Strains and Host Susceptibility Genes in Korean Patients with Pulmonary TB. This study seeks to characterize MDR and XDR TB isolates and their contribution to human disease and has over 770 subjects enrolled. A substudy of this protocol has been investigating biomarkers of disease response in collaboration with University of Stellenbosch and Rutgers Biomedical and Health Sciences. The Natural History study has allowed a number of basic biology questions about the differences in drug resistant and drug sensitive TB to be addressed by whole genome sequencing. We are also studying the mechanism of action of various TB drugs and how mutations in the Mtb genome confer resistance and affect fitness. As part of the TB Clinical Diagnostics Research Consortium (TB-CDRC), we used 200 isolates collected under this protocol to investigate the performance of a microtiter plate-based drug susceptibility assay called SENSITITREMYCOTB. This test gives minimum inhibitory concentration (MIC) results to both first and second line agents faster than traditional methods. Several new next generation GeneXpert tests are being developed. For rifampin resistance, more mutations using a unique sloppy beacon approach are being added. An XDR cartridge is under development to detect fluoroquinolone and kanamycin resistance. In an ongoing analysis, we are examining the risk factors associated with treatment outcomes among new TB cases (primarily drug sensitive) and retreatment cases (often MDR TB patients). Preliminary results show that factors associated with poor outcomes are similar between the two groups and include diabetes mellitus, smoking, low BMI, far advanced disease on CXR at presentation, and having MDR TB. (2) NIAID 07-I-N041: A Randomized, Double-blind, Placebo-controlled Pilot Study of Metronidazole Combined with Anti-TB Chemotherapy vs. Anti-TB Chemotherapy with Placebo in Subjects with Pulmonary MDR-TB. The importance of anaerobic activity in candidate TB drugs is under investigation in this study. In 2009, the trial closed to enrollment after 35 subjects enrolled because of excessive peripheral neuropathies in the metronidazole arm. The study is now complete and the overall analysis has been published. Although more subjects in the metronidazole arm converted their sputum smear (P=0.04) and liquid culture (P=0.04) to negative at one month compared to placebo, these differences were lost by two months. Overall, 81% showed clinical success six months after stopping therapy, with no differences by arm. However, subjects in the metronidazole arm were 4.3 fold (95% CI 1.1-17.1) more likely to develop peripheral neuropathies. Metronidazole may have increased early sputum smear and culture conversion but was too neurotoxic to use over the longer tem. Newer nitroimidazoles with both aerobic and anaerobic activity, now in clinical trials, may increase the sterilizing potency of future treatment regimens. Additional analyses are ongoing to determine whether or not PET/CT can serve as an early radiographic biomarker of treatment response. Preliminary results suggest that change in PET total glycolytic activity from baseline to two months and change in total abnormal lung volume on quantitative CT analysis from baseline to six months both are predictive of final treatment outcomes six months after the end of therapy. (3) NIAID 08-I-N167: A Phase 2a, Randomized, 2 Arm, Open-label, Clinical Trial of the Efficacy of Linezolid Combined with Anti-TB Therapy in Subjects with Pulmonary XDR-TB. The major aim of this study is to evaluate the efficacy, safety and tolerability of one of the drugs of last resort for XDR TB patients, linezolid (LZD, Zyvox, Pfizer). This trial opened in 12/2008 and has enrolled 39 evaluable subjects with XDR TB and closed to enrollment in 7/2010. By four months, 15/19 (79%) subjects in the immediate-start arm and 7/20 (35%) subjects in the delayed-start arm achieved culture conversion (P=0.001). 34/39 (87%) subjects achieved culture negative sputum within six months of adding LZD to their failing drug regimens. Among the 38 subjects exposed to LZD, 31 (82%) experienced clinically significant adverse events (AEs) possibly or probably related to LZD that resulted in 3 subjects discontinuing therapy. Subjects who dose reduced to 300 mg/day after the second randomization had fewer adverse events than subjects who continued taking 600 mg/day. Twenty-six subjects successfully completed therapy and remain relapse-free. Four cases of acquired resistance to LZD have been observed thus far. LZD is highly effective at achieving culture conversion among subjects with treatment-refractory pulmonary XDR tuberculosis but adverse events must be monitored carefully. Due to these results, LZD is now an insurance reimbursable TB drug in Korea. (4) NIAID 09-I-N061; Pharmacokinetics of Standard First and Second Line Anti-TB Drugs in the Lung and Lesions of Subjects Elected for Resection Surgery. This is a multicenter study of the differential penetration of TB chemotherapeutics into pulmonary TB lesions. The study opened in 2010 and 10 subjects have been enrolled at Asan Medical Center, 4 at Pusan National University Hospital, and 3 at National Medical Center. The study will further define the relationship between pathology and drug penetration in the types of lesions commonly seen in TB patients and follow up work we have conducted on lesion penetration in rabbits. Initial imaging mass spectrometry results show similar drug distribution results to those in the rabbit model, with concentration of moxifloxacin in the rim of lesions. (5) NIAID 12-I-N036; Risk Stratification in Latent Tuberculosis: PET/CT Findings in TB Contacts and the Effect of Preventive Treatment. The primary purpose of this study is to determine whether or not FDG uptake by PET scanning, as well as other biomarkers, can predict activation of latent TB infection in close contacts of active TB cases. This is a critically important issue as no biomarker currently can predict TB reactivation. Only about 10% of people latently infected with TB will develop active TB, thus 90% of exposed people are needlessly treated with a potentially hepatotoxic drug. The recruitment into this study has been very slow and a very similar study is launching in South Africa in collaboration with TRS investigators and may replace this study if recruitment is successful. (6) In FY2014, a new study initiated, titled Feasibility and accuracy of a novel Xpert cartridge for rapid molecular detection of drug resistant Mycobacterium tuberculosis in sputum (DMID Protocol Number 13-0029; DMID Funding Mechanism: Award Number N01AI90500C). This study is being conducted in conjunction with Susan Dorman at Johns Hopkins University under a grant from DMID. The primary objective of this prospective, cross-sectional study is to estimate the sensitivity and specificity of the investigational Xpert cartridge for detection of M. tuberculosis resistance to isoniazid, fluoroquinolones, and aminoglycosides. 550 subjects will be enrolled in Zhengzhou, Henan Province and Seoul, South Korea.

该项目是TRS/LCID/NIAID，韩国卫生与福利部，韩国疾病预防控制中心和韩国共和国Yonsei大学医学院之间的合作。这些合作者共同建立了国际结核病研究中心（ITRC），该研究中心（ITRC）在实验室设施中管理财务和科学活动，包括功能齐全的BSL3实验室设施。此外，正在与ASAN医疗中心，三星医学中心，帕桑国立大学医院和国家医学中心合作进行研究。 正在进行的特定协议驱动调查包括： （1）NIAID 05-I-N069：韩国肺结核患者中MDR-TB菌株和宿主易感基因的自然史研究。这项研究旨在表征MDR和XDR TB分离株及其对人类疾病的贡献，并拥有770多名受试者。该方案的一种方法一直在与Stellenbosch大学和Rutgers生物医学和健康科学合作调查疾病反应的生物标志物。自然历史研究允许通过整个基因组测序来解决有关耐药性和药物敏感结核病差异的许多基本生物学问题。我们还研究了各种结核病药物的作用机理，以及MTB基因组中的突变如何赋予抗性并影响适应性。作为结核病临床诊断研究联盟（TB-CDRC）的一部分，我们使用了根据该方案收集的200个分离物来研究基于微滴定板的药物敏感性测定的性能，称为sensitremycotb。该测试比传统方法更快地给第一线和第二线剂的抑制浓度（MIC）结果。正在开发一些新的下一代GenExpert测试。对于利福平耐药性，正在添加更多使用独特的马虎信标方法的突变。正在开发XDR弹药筒，以检测氟喹诺酮和卡纳霉素耐药性。在正在进行的分析中，我们正在研究与新结核病病例（主要是药物敏感）和撤退病例（通常是MDR结核病患者）中与治疗结果相关的危险因素。初步结果表明，两组之间与较差的结果相关的因素包括糖尿病，吸烟，低BMI，表现时在CXR上进行的远晚期疾病以及MDR TB。 （2）NIAID 07-I-N041：甲硝唑的随机，双盲，安慰剂对照的初步研究，结合了抗TB化学疗法与抗TB化学疗法，在患有肺MDR-TB受试者中的安慰剂。在这项研究中，正在研究厌氧活性在候选结核病药物中的重要性。 2009年，由于甲硝唑组中的周围神经病过多，该试验在35名受试者入学后入学。该研究现已完成，并且已经发布了整体分析。尽管与安慰剂相比，甲硝唑手臂中的更多受试者将其痰涂片（p = 0.04）和液体培养（p = 0.04）转化为阴性，但这些差异却损失了两个月。总体而言，有81％的人在停止治疗六个月后表现出临床成功，而没有差异。但是，甲硝唑组中的受试者为4.3倍（95％CI 1.1-17.1），更有可能发展周围神经病。甲硝唑可能增加了早期的痰液涂片和培养转化率，但神经毒性过于较长的TEM。如今，在临床试验中，具有有氧和厌氧活性的新硝基咪唑都可能会增加未来治疗方案的消毒效力。正在进行其他分析，以确定PET/CT是否可以作为治疗反应的早期射线照相生物标志物。初步结果表明，PET总糖酵解活性从基线到两个月的变化，以及从基线到六个月的定量CT分析中总肺部异常量的变化，这两者都可以预测治疗结束后六个月后的最终治疗结果。 （3）NIAID 08-I-N167：2A期2A，随机，2个ARM，开放标签，LineZolid疗效的临床试验与抗TB治疗在肺XDR-TB受试者中结合使用。这项研究的主要目的是评估XDR TB患者最后一种药物之一，Linezolid（LZD，Zyvox，Pfizer）的疗效，安全性和耐受性。该试验于12/2008开放，并招募了39名可评估的受试者，并在7/2010年关闭了入学率。到四个月，即时起步组中的15/19（79％）受试者，延迟启动臂中的7/20（35％）受试者实现了培养conversion依（p = 0.001）。 34/39（87％）受试者在将LZD添加到失败的药物方案中后的六个月内实现了培养物负痰。在暴露于LZD的38名受试者中，有31名（82％）可能与LZD有关或可能与LZD相关的临床意义不良事件（AES），导致3名中断治疗的受试者。第二个随机分组后剂量降低至300 mg/天的受试者的不良事件少于继续服用600 mg/天的受试者。 26名受试者成功地完成了治疗，并保持无复发。到目前为止，已经观察到了四例对LZD的抗性。 LZD非常有效地在患有治疗症状的肺XDR结核病患者之间实现培养物转化，但必须仔细监测不良事件。由于这些结果，LZD现在是韩国可偿还的TB药物。 （4）NIAID 09-I-N061;肺中标准第一和第二线抗TB药物的药代动力学以及当选为切除手术的受试者的病变。 这是TB化学治疗剂在肺结核病变中的差异渗透的多中心研究。这项研究于2010年开业，已在ASAN医疗中心，Pusan国立大学医院的4个和3个在国家医学中心招募了10个科目。这项研究将进一步定义结核病患者常见病变类型的病理与药物渗透之间的关系，并随访了我们在兔子中进行病变渗透而进行的。初始成像的质谱结果显示出与兔模型中的药物分布相似的结果，在病变的边缘中，莫西沙星浓度浓度。 （5）NIAID 12-I-N036;潜在结核病的风险分层：结核病接触中的PET/CT发现以及预防治疗的效果。这项研究的主要目的是确定PET扫描以及其他生物标志物是否可以预测潜在TB感染在活动性结核病病例的密切接触中激活潜在的TB感染。这是一个至关重要的问题，因为目前没有生物标志物可以预测结核病重新激活。只有大约10％的受结核病感染的人会发展为活跃的结核病，因此，有90％的暴露者受到潜在的肝毒性药物的治疗。这项研究的招募非常缓慢，与TRS研究人员合作，在南非发起了非常相似的研究，如果招聘成功，可能会取代这项研究。 （6）在2014财年，一项新的研究发起了一项新型XPERT弹药筒的可行性和准确性，用于快速分子检测痰液中耐药性分枝杆菌结核病（DMID协议编号13-0029; DMID资金机制：奖励编号N01AI90500C）。这项研究是由约翰·霍普金斯大学（Johns Hopkins University）的苏珊·多曼（Susan Dorman）与DMID的赠款一起进行的。这项前瞻性，横断面研究的主要目的是估计研究性XPERT弹药筒的灵敏度和特异性，以检测结核分枝杆菌对异烟肼，氟喹诺酮类和氨基糖苷的抗性。 550名受试者将在朝鲜省的郑州和韩国首尔招收。