非酒精性脂肪性肝炎新药临床试验方案的系统评价

黄樱硕; 魏巍; 佟小非; 孙亚朦; 张健雄; 董瑞华; 贾继东; 尤红

doi:10.3969/j.issn.1001-5256.2022.04.012

非酒精性脂肪性肝炎新药临床试验方案的系统评价

DOI: 10.3969/j.issn.1001-5256.2022.04.012

黄樱硕^a,
魏巍^b,
佟小非^{c, d, e},
孙亚朦^{c, d, e},
张健雄^a,
董瑞华^a, , ,,
贾继东^{c, d, e},
尤红^{c, d, e, , ,}

a.
首都医科大学附属北京友谊医院研究型病房，北京 100050
b.
首都医科大学附属北京友谊医院临床流行病学与循证医学研究室，北京 100050
c.
首都医科大学附属北京友谊医院肝病中心，北京 100050
d.
首都医科大学附属北京友谊医院肝硬化转化医学北京市重点实验室，北京 100050
e.
首都医科大学附属北京友谊医院国家消化系统疾病临床医学研究中心，北京 100050

基金项目:

国家自然科学基金重点项目 (82130018);

北京市医院管理局消化内科学科协同发展中心消化专项重点项目 (XXZ03);

北京市研究型病房示范建设单位项目 (BCRW202010)

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：尤红、贾继东负责选题及文章结构设计；黄樱硕、魏巍负责检索数据库、筛选文献及提取资料；黄樱硕、佟小非负责撰写文章并修改；董瑞华、孙亚朦、张健雄负责对结果进行分析和讨论；黄樱硕参与完成初稿的撰写。

详细信息

通信作者:
董瑞华，ruihua_dong_rw@163.com

尤红，youhongliver@ccmu.edu.com

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出版历程
- 收稿日期: 2021-09-07
- 录用日期: 2021-10-15
- 出版日期: 2022-04-20

Clinical trial protocols of new drugs for nonalcoholic steatohepatitis: A systematic review

Yingshuo HUANG^a,
Wei WEI^b,
Xiaofei TONG^{c, d, e},
Yameng SUN^{c, d, e},
Jianxiong ZHANG^a,
Ruihua DONG^{a
, ,
,},
Jidong JIA^{c, d, e},
Hong YOU^{c, d, e
, ,
,}

a.
Department of Research Ward, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
b.
Department of Clinical Epidemiology and EBM, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
c.
Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
d.
Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
e.
National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China

Research funding:

National Natural Science Foundation of China (82130018);

Digestive Medical Coordinated Development Center of Beijing Municipal Administration of Hospitals (XXZ03);

Beijing research ward demonstration construction project (BCRW202010)

More Information

Corresponding author: DONG Ruihua, ruihua_dong_rw@163.com(ORCID: 0000-0003-3463-5023); YOU Hong, youhongliver@ccmu.edu.com(ORCID: 0000-0001-9409-1158)

摘要

摘要: 目的描述国内外非酒精性脂肪性肝炎(NASH)新药临床试验的注册情况及临床试验特点，为NASH新药临床试验的设计和开展提供参考依据。方法检索美国临床实验数据库、中国临床试验注册中心、国家药品监督管理局药品审评中心，检索日期为建库至2021年8月6日，以“非酒精性脂肪性肝炎”和“NASH”作为关键词，纳入以NASH作为适应证的新药注册试验或干预性研究，并除外肝硬化。由两位研究者独立检索并筛选文献，提取相关信息。结果共纳入196项NASH新药注册试验或干预试验(174项国外注册试验，22项国内注册试验)，注册量呈增长趋势，其中Ⅰ期、Ⅰ~Ⅱ期(包括Ⅰb/Ⅱa)、Ⅱ期、Ⅱ~Ⅲ期、Ⅲ期临床试验分别为45项(23.0%)、8项(4.1%)、112项(57.1%)、4项(2.0%)、19项(9.7%)。药物类型以法尼酯X受体类、成纤维细胞生长因子类、过氧化物酶体增殖物激活受体激动剂、胰高血糖素样肽-1类为主，分别为16项(8.16%)、14项(7.14%)、11项(5.61%)、13项(6.63%)。欧美地区申办方发起的NASH创新药试验最多，中国(含台湾地区)近年来的自主创新药临床试验数量逐渐增加，单中心与多中心数量分布近似。其中以NASH患者为受试对象的试验中以病理、影像学、临床诊断作为主要入选标准的试验数量分别为125项、66项和42项。Ⅰ期临床试验主要评价指标为安全性、耐受性和药代动力学指标，Ⅱ、Ⅲ期临床试验主要评价指标为安全性和有效性。中国(含台湾地区)本土NASH创新药物注册试验数量较少但逐渐增长，中药相对化学药物的新药临床试验较少。结论国际NASH创新药临床试验注册量增长较为显著，但多处于早期阶段，入选标准和评价指标差异较大，缺少较统一的衡量指标，新型试验设计较少。国内NASH新药临床试验相对欧美国家数量较少，呈增长趋势。
- 非酒精性脂肪性肝炎 /
- 临床试验 /
- 评价研究
Abstract: Objective To describe the characteristics and registration status of clinical trials of new drugs for nonalcoholic steatohepatitis (NASH), and to provide a reference for the design and implementation of clinical trials of new drugs for NASH. Methods The U.S. Clinical Trials Database, China Clinical Trial Registry, and Center for Drug Evaluation, National Medical Products Administration, were searched for clinical trials of new drug registration and interventional studies with NASH as the indication published up to August 6, 2021, using NASH in English and Chinese characters as the keywords, and liver cirrhosis was excluded. Two researchers independently searched and screened the articles to extract relevant information. Results A total of 196 clinical trials of new drug registration or interventional studies for NASH were included, among which there were 174 trials registered abroad and 22 trials registered in China, and the number of registrations tended to increase year by year. The numbers of phase Ⅰ, phase Ⅰ/Ⅱ(including Ⅰb/Ⅱa), phase Ⅱ, phase Ⅱ/Ⅲ, and phase Ⅲ clinical trials were 45(23.0%), 8(4.1%), 112(57.1%), 4(2.0%), and 19(9.7%), respectively. The main drug types included farnesoid X receptors, fibroblast growth factors, peroxisome proliferator-activated receptor agonists, and glucagon-like peptide-1, with numbers of 16(8.16%), 14(7.14%), 11(5.61%), and 13(6.63%), respectively. The clinical trials of innovative drugs for NASH initiated by the sponsors in European and American regions accounted for the highest proportion, and there was a gradual increase in the number of clinical trials of innovative drugs in China in recent years, with a similar distribution of single-center and multicenter clinical trials. As for the trials with NASH patients as subjects, the numbers of trials with pathology, imaging, and clinical diagnosis as the main inclusion criteria were 125, 66, and 42, respectively. Phase Ⅰ clinical trials used safety, tolerability, and pharmacokinetic parameters as the main assessment indices, while phase Ⅱ and phase Ⅲ clinical trials often used safety and efficacy as the main assessment indices. The number of clinical trials for the registration of innovative drugs for NASH was relatively low but kept increasing in China, and there were fewer clinical trials of innovative traditional Chinese medicine drugs compared with innovative chemical drugs. Conclusion There is a significant increase in the registration of international clinical trials of innovative drugs for NASH, and most of these trials are in the early phases, with large differences in inclusion criteria and assessment indices, a lack of unified evaluation indices, and relatively few trials with new designs. There are fewer clinical trials of innovative drugs for NASH in China than in European and American countries, and the number of such trials is gradually increasing in China.
- Nonalcoholic Steatohepatitis /
- Clinical Trial /
- Evaluation Studies

HTML全文

图 1 筛选流程图

Figure 1. Screening flow chart

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图 2 申办方公司所在国家的注册试验数量

Figure 2. The number of clinical trials in different countries where sponsor companies located

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图 3 试验状态分类的数量分布

Figure 3. Distribution of status of trials

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图 4 注册试验数量随年份分布情况

Figure 4. Numbers of registered trials distributed by year

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图 5 NASH新药试验的靶点类型

Figure 5. Types of targets for NASH drug trials

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图 6 NASH新药试验病理评价诊断标准的有效时间

Figure 6. Effective time of pathological assessment for NASH drug trials

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参考文献(21)

[1]	National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, Chinese Medical Association, Fatty Liver Expert Committee, Chinese Medical Doctor Association. Guidelines of prevention and treatment for nonalcoholic fatty liver disease: A 2018 update[J]. J Clin Hepatol, 2018, 34(5): 947-957. DOI: 10.3969/j.issn.1001-5256.2018.05.007. 中华医学会肝病学分会脂肪肝和酒精性肝病学组, 中国医师协会脂肪性肝病专家委员会. 非酒精性脂肪性肝病防治指南(2018年更新版)[J]. 临床肝胆病杂志, 2018, 34(5): 947-957. DOI: 10.3969/j.issn.1001-5256.2018.05.007.
[2]	YOUNOSSI ZM, KOENIG AB, ABDELATIF D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes[J]. Hepatology, 2016, 64(1): 73-84. DOI: 10.1002/hep.28431.
[3]	SANYAL AJ, FRIEDMAN SL, MCCULLOUGH AJ, et al. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: Findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop[J]. Hepatology, 2015, 61(4): 1392-1405. DOI: 10.1002/hep.27678.
[4]	LAZARIDIS N, TSOCHATZIS E. Current and future treatment options in non-alcoholic steatohepatitis (NASH)[J]. Expert Rev Gastroenterol Hepatol, 2017, 11(4): 357-369. DOI: 10.1080/17474124.2017.1293523.
[5]	ANANIA FA, DIMICK-SANTOS L, MEHTA R, et al. Nonalcoholic steatohepatitis: Current thinking from the division of hepatology and nutrition at the food and drug administration[J]. Hepatology, 2021, 73(5): 2023-2027. DOI: 10.1002/hep.31687.
[6]	RINELLA ME, TACKE F, SANYAL AJ, et al. Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD[J]. J Hepatol, 2019, 71(4): 823-833. DOI: 10.1016/j.jhep.2019.04.019.
[7]	China Food and Drug Administration. Guidelines for clinical trials of drugs for the treatment of non alcoholic steatohepatitis[EB/OL]. [2019-12-30]. http://www.nmpa.gov.cn/WS04/CL2138/372284.html. 国家药品食品监督管理总局. 非酒精性脂肪性肝炎治疗药物临床试验指导原则(试行)[EB/OL]. [2019-12-30]. http://www.nmpa.gov.cn/WS04/CL2138/372284.html.
[8]	KLEINER DE, BRUNT EM, van NATTA M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease[J]. Hepatology, 2005, 41(6): 1313-1321. DOI: 10.1002/hep.20701.
[9]	KONERMAN MA, JONES JC, HARRISON SA. Pharmacotherapy for NASH: Current and emerging[J]. J Hepatol, 2018, 68(2): 362-375. DOI: 10.1016/j.jhep.2017.10.015.
[10]	REIMER KC, WREE A, RODERBURG C, et al. New drugs for NAFLD: Lessons from basic models to the clinic[J]. Hepatol Int, 2020, 14(1): 8-23. DOI: 10.1007/s12072-019-10001-4.
[11]	TONG XF, SUN YM, YOU H. Evaluation of clinical endpoints in new drug research and development for nonalcoholic steatohepatitis[J]. J Clin Hepatol, 2021, 37(6): 1249-1253. DOI: 10.3969/j.issn.1001-5256.2021.06.003. 佟小非, 孙亚朦, 尤红. 非酒精性脂肪性肝炎新药研发临床终点评价[J]. 临床肝胆病杂志, 2021, 37(6): 1249-1253. DOI: 10.3969/j.issn.1001-5256.2021.06.003.
[12]	DAVISON BA, HARRISON SA, COTTER G, et al. Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials[J]. J Hepatol, 2020, 73(6): 1322-1332. DOI: 10.1016/j.jhep.2020.06.025.
[13]	CAUSSY C, REEDER SB, SIRLIN CB, et al. Noninvasive, quantitative assessment of liver fat by MRI-PDFF as an endpoint in NASH trials[J]. Hepatology, 2018, 68(2): 763-772. DOI: 10.1002/hep.29797.
[14]	JAYAKUMAR S, MIDDLETON MS, LAWITZ EJ, et al. Longitudinal correlations between MRE, MRI-PDFF, and liver histology in patients with non-alcoholic steatohepatitis: Analysis of data from a phase Ⅱ trial of selonsertib[J]. J Hepatol, 2019, 70(1): 133-141. DOI: 10.1016/j.jhep.2018.09.024.
[15]	HOOKER JC, HAMILTON G, PARK CC, et al. Inter-reader agreement of magnetic resonance imaging proton density fat fraction and its longitudinal change in a clinical trial of adults with nonalcoholic steatohepatitis[J]. Abdom Radiol (NY), 2019, 44(2): 482-492. DOI: 10.1007/s00261-018-1745-3.
[16]	SASSO M, AUDIÈRE S, KEMGANG A, et al. Liver steatosis assessed by controlled attenuation parameter (CAP) measured with the XL probe of the FibroScan: A Pilot study assessing diagnostic accuracy[J]. Ultrasound Med Biol, 2016, 42(1): 92-103. DOI: 10.1016/j.ultrasmedbio.2015.08.008.
[17]	VILAR-GOMEZ E, MARTINEZ-PEREZ Y, CALZADILLA-BERTOT L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis[J]. Gastroenterology, 2015, 149(2): 367-378. e5; quiz e14-e15. DOI: 10.1053/j.gastro.2015.04.005.
[18]	ROMERO-GÓMEZ M, ZELBER-SAGI S, TRENELL M. Treatment of NAFLD with diet, physical activity and exercise[J]. J Hepatol, 2017, 67(4): 829-846. DOI: 10.1016/j.jhep.2017.05.016.
[19]	SANYAL AJ, BRUNT EM, KLEINER DE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis[J]. Hepatology, 2011, 54(1): 344-353. DOI: 10.1002/hep.24376.
[20]	RATZIU V. A critical review of endpoints for non-cirrhotic NASH therapeutic trials[J]. J Hepatol, 2018, 68(2): 353-361. DOI: 10.1016/j.jhep.2017.12.001.
[21]	LICHTINGHAGEN R, PIETSCH D, BANTEL H, et al. The enhanced liver fibrosis (ELF) score: Normal values, influence factors and proposed cut-off values[J]. J Hepatol, 2013, 59(2): 236-242. DOI: 10.1016/j.jhep.2013.03.016.