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、韩国卫生福利部、韩国疾病预防控制中心和韩国延世大学医学院之间的合作项目。这些合作者共同建立了国际结核病研究中心 (ITRC)，负责管理实验室设施内的财务和科学活动，包括功能齐全的 BSL3 实验室设施。此外，研究还与位于首尔的峨山医疗中心、三星医疗中心、釜山国立大学医院和国家医疗中心合作进行。 正在进行的具体协议驱动的调查包括： (1) NIAID 05-I-N069：韩国肺结核患者耐多药结核菌株和宿主易感基因的自然史研究。这项研究旨在描述 MDR 和 XDR TB 菌株的特征及其对人类疾病的影响，并已招募了 770 多名受试者。该协议的一项子研究一直在与斯泰伦博斯大学和罗格斯大学生物医学和健康科学合作研究疾病反应的生物标志物。自然历史研究使得有关耐药性和药物敏感性结核病差异的许多基本生物学问题可以通过全基因组测序得到解决。我们还在研究各种结核病药物的作用机制，以及结核分枝杆菌基因组的突变如何赋予耐药性并影响健康。作为结核病临床诊断研究联盟 (TB-CDRC) 的一部分，我们使用根据该方案收集的 200 个分离株来研究基于微量滴定板的药物敏感性测定（称为 SENSITITREMYCOTB）的性能。该测试比传统方法更快地为一线和二线药物提供最低抑菌浓度 (MIC) 结果。一些新的下一代 GeneXpert 测试正在开发中。对于利福平耐药性，正在使用独特的草率信标方法添加更多突变。正在开发一种 XDR 试剂盒，用于检测氟喹诺酮和卡那霉素耐药性。在一项正在进行的分析中，我们正在研究与新结核病病例（主要是药物敏感）和再治疗病例（通常是耐多药结核病患者）的治疗结果相关的风险因素。初步结果显示，两组之间与不良结果相关的因素相似，包括糖尿病、吸烟、低体重指数、CXR 就诊时疾病处于晚期以及患有耐多药结核病。 (2) NIAID 07-I-N041：在肺耐多药结核病受试者中进行甲硝唑联合抗结核化疗与抗结核化疗联合安慰剂的随机、双盲、安慰剂对照初步研究。本研究正在调查候选结核病药物中厌氧活性的重要性。 2009 年，由于甲硝唑组出现过度周围神经病变，35 名受试者入组，该试验结束入组。该研究现已完成，总体分析已发表。尽管与安慰剂组相比，甲硝唑组中有更多受试者在 1 个月内将痰涂片 (P=0.04) 和液体培养 (P=0.04) 转为阴性，但这些差异在两个月后消失。总体而言，81% 的患者在停止治疗六个月后表现出临床成功，各组之间没有差异。然而，甲硝唑组的受试者发生周围神经病变的可能性增加了 4.3 倍（95% CI 1.1-17.1）。甲硝唑可能会增加早期痰涂片和培养物转化，但神经毒性太大，无法长期使用。具有需氧和厌氧活性的新型硝基咪唑目前正在临床试验中，可能会提高未来治疗方案的灭菌效力。正在进行更多分析以确定 PET/CT 是否可以作为治疗反应的早期放射学生物标志物。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定量 CT 分析中总异常肺容量从基线到六个月的变化均可预测治疗结束后 6 个月的最终治疗结果。 (3) NIAID 08-I-N167：一项 2a 期、随机、2 臂、开放标签临床试验，研究利奈唑胺联合抗结核治疗对肺广泛耐药结核病患者的疗效。本研究的主要目的是评估广泛耐药结核病患者的最后手段之一利奈唑胺（LZD、Zyvox、辉瑞）的疗效、安全性和耐受性。该试验于 2008 年 12 月开始，已招募了 39 名可评估的广泛耐药结核受试者，并于 2010 年 7 月结束招募。到四个月时，立即开始组中 15/19 (79%) 的受试者和延迟开始组中 7/20 (35%) 的受试者实现了培养转化 (P=0.001)。 34/39 (87%) 的受试者在失败的药物治疗方案中添加 LZD 后六个月内痰培养阴性。在暴露于 LZD 的 38 名受试者中，31 名 (82%) 经历了可能或很可能与 LZD 相关的临床显着不良事件 (AE)，导致 3 名受试者停止治疗。第二次随机分组后剂量减少至 300 毫克/天的受试者比继续服用 600 毫克/天的受试者发生的不良事件更少。二十六名受试者成功完成治疗并且保持无复发。迄今为止，已观察到四例 LZD 获得性耐药病例。 LZD 对于难治性 XDR 肺结核患者实现培养转化非常有效，但必须仔细监测不良事件。由于这些结果，LZD 现在是韩国的一种保险可报销结核病药物。 (4)NIAID 09-I-N061；标准一线和二线抗结核药物在选择进行切除手术的受试者的肺部和病变中的药代动力学。 这是一项关于结核病化疗药物对肺部结核病灶的差异渗透的多中心研究。该研究于 2010 年开始，共有 10 名受试者在牙山医疗中心入组，4 名受试者在釜山国立大学医院入组，3 名受试者在国立医疗中心入组。该研究将进一步明确结核病患者常见病灶类型的病理学与药物渗透之间的关系，并对我们在兔子病灶渗透方面进行的后续工作进行跟踪。初始成像质谱结果显示与兔子模型相似的药物分布结果，莫西沙星在病灶边缘集中。 (5)NIAID 12-I-N036；潜伏性结核病的风险分层：结核病接触者的 PET/CT 结果和预防治疗的效果。本研究的主要目的是确定 PET 扫描摄取的 FDG 以及其他生物标志物是否可以预测活动性结核病例密切接触者中潜伏性结核感染的激活。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的重新激活。只有约 10% 的潜伏感染结核病患者会发展为活动性结核病，因此 90% 的暴露人群不必要地接受了潜在肝毒性药物的治疗。这项研究的招募工作非常缓慢，南非正在与 TRS 研究人员合作开展一项非常类似的研究，如果招募成功，可能会取代这项研究。 (6) 2014 财年，启动了一项新研究，题为用于快速分子检测痰中耐药结核分枝杆菌的新型 Xpert 试剂盒的可行性和准确性（DMID 方案编号 13-0029；DMID 资助机制：奖项编号 N01AI90500C）。这项研究是在 DMID 的资助下与约翰·霍普金斯大学的 Susan Dorman 联合进行的。这项前瞻性横断面研究的主要目的是评估研究性 Xpert 试剂盒检测结核分枝杆菌对异烟肼、氟喹诺酮类药物和氨基糖苷类药物耐药性的敏感性和特异性。河南郑州和韩国首尔将招收550名受试者。