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非酒精性脂肪性肝炎治疗药物临床试验指导原则(试行)(2019年第92号)

FABUSHIJIAN:2022-03-02  LIULAN:CI

  引言:非酒精性脂肪性肝炎(NASH)又称代谢性脂肪性肝炎,是病理变化与酒精性肝炎相似但无过量饮酒史的临床综合征,好发于中年特别是超重肥胖个体。药监局于2019年12月20日发布非酒精性脂肪性肝炎治疗药物临床试验技术指导原则,本指导原则由药品监督管理部门与临床研究者共同讨论制定,为非酒精性脂肪性肝炎(Nonalcoholic Steatohepatitis,NASH)治疗药物的研发提供技术建议。本指导原则只针对NASH伴有显著肝纤维化(F2~F4)(包括代偿期肝硬化)的成人患者,不涉及失代偿期肝硬化或儿童患者。

  附件:

非酒精性脂肪性肝炎治疗药物临床试验指导原则(试行)
(2019年第92号)

  一、适用范围

  BENZHIDAOYUANZEYOUYAOPINJIANDUGUANLIBUMENYULINCHUANGYANJIUZHEGONGTONGTAOLUNZHIDING,WEIFEIJIUJINGXINGZHIFANGXINGGANYAN(Nonalcoholic Steatohepatitis,NASH)ZHILIAOYAOWUDEYANFATIGONGJISHUJIANYI。BENZHIDAOYUANZEZHIZHENDUINASHBANYOUXIANZHUGANXIANWEIHUA(F2~F4)(BAOKUODAICHANGQIGANYINGHUA)DECHENGRENHUANZHE,BUSHEJISHIDAICHANGQIGANYINGHUAHUOERTONGHUANZHE。

  BENZHIDAOYUANZESHIYONGYUHUAXUEYAOPINHEZHILIAOYONGSHENGWUZHIPINDEYAOWUYANFA,JINZUOWEITUIJIANXINGJIANYI。ZAIYINGYONGBENZHIDAOYUANZESHI,HAIYINGTONGSHICANKAOGUOJIRENYONGYAOPINZHUCEJISHUXIEDIAOHUI(The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use,ICH)HEQITAGUONEIWAIYIFABUDEXIANGGUANJISHUZHIDAOYUANZE。

  BENZHIDAOYUANZEJIANGJIYUKEXUEYANJIUJINZHANJINYIBUGENGXIN。JIANYUNASHZHILIAOYAOWULINCHUANGYANFAZHONGGUANJIANYAOSUDEJINZHANHEGENGXINXUNSU,BENZHIDAOYUANZEJINDAIBIAODANGQIANJIANYI。

  二、概述

  BENZHIDAOYUANZEZHUYAOTAOLUNNASHZHILIAOYAOWUYANFAZHONGLINCHUANGSHIYANSHEJIDEZHONGDIANGUANZHUNEIRONG。GUANYULINCHUANGSHIYANSHEJIHUOTONGJIXUEFENXIDEYIBANXINGWENTIKECANKAOQITAXIANGGUANZHIDAOYUANZE。

  (YI)DINGYI

  FEIJIUJINGXINGZHIFANGXINGGANBING(Nonalcoholic Fatty Liver Disease,NAFLD)SHIYIZHONGYUYIDAOSUDIKANGHEYICHUANYIGANMIQIEXIANGGUANDEDAIXIEYINGJIXINGGANZANGSUNSHANG,JIBINGPUBAOKUOFEIJIUJINGXINGGANZHIFANGBIAN(Nonalcoholic Hepatic Steatosis)(DENGTONGFEIJIUJINGXINGZHIFANGGANNAFL〔Nonalcoholic fatty liver〕)、FEIJIUJINGXINGZHIFANGXINGGANYAN(Nonalcoholic Steatohepatitis,NASH)JINASHXIANGGUANGANYINGHUAHEGANXIBAOAI。NASHBIAOXIANWEI5%YISHANGDEGANXIBAOZHIFANGBIANHEBINGXIAOYENEIYANZHENGHEGANXIBAOQIQIUYANGBIANXING。

  (ER)LIUXINGBINGXUE

  NAFLDSHIQUANQIULIUXINGDEZHUYAOGANZANGJIBINGZHIYI,YOUWENXIANBAODAO,QUANQIUHUANBINGLVWEI25.24%(95% CI :22.10-28.65),QIEHUANBINGLVZHUNIANZENGJIA。LAIZISHANGHAI、BEIJINGDENGDIQUDELIUXINGBINGXUEDIAOCHAJIEGUOXIANSHI,PUTONGCHENGRENBXINGCHAOSHENGZHENDUANDENAFLDHUANBINGLV10NIANQIJIANCONG15%ZENGJIADAO31%YISHANG。NASHZAIHEBINGDAIXIEZONGHEZHENG、2XINGTANGNIAOBINGDENAFLDHUANZHEZHONGJIANCHULVGAO。NASHSHIDAOZHIGANYINGHUADEZHUYAOYUANYINZHIYI,NASHHUANZHE10~15NIANNEIGANYINGHUAFASHENGLVGAODA15%~25%。XINXUEGUANJIBING、EXINGZHONGLIUHEGANYINGHUASHIDAICHANGSHIYINQINASHHUANZHESIWANGDECHANGJIANYUANYIN。

  (SAN)ZHILIAOYAOWU

  ZHILIAOMUBIAO:ZUIZHONGMUDESHIYANHUAN、ZUZHI、NIZHUANNASHDEJINZHAN,GAISHANLINCHUANGJIEJU,BAOKUOJIANGDIGANYINGHUAJIQIBINGFAZHENGDEFASHENG,JIANGDIGANYIZHIDEXUQIU,TIGAOCUNHUOLV,GAISHANSHENGHUOZHILIANGDENG。

  ZHILIAOYAOWU:MUQIANSHANGWUTONGGUOSUIJIDUIZHAOLINCHUANGSHIYANQUEZHENGYOUXIAOXINGHEANQUANXINGDEZHILIAOYAOWUSHANGSHI。

  三、临床试验设计

  (YI)ZONGTIKAOLV

  YAOWUYANFALINCHUANGSHIYANDESHEJIJIYULINCHUANGSHIYANMUDEERDING。GENJUZHILIAONASHYAOWUBADIANBUTONG,ZHIDINGLINCHUANGSHIYANFANGAN。

  1.SHOUSHIZHE

  NASHZHENDUAN:JINGUANGANZUZHIXUEJIANCHACUNZAIYOUCHUANGXING、QUYANGHEPINGJIAWUCHADENGJUXIANXING,DANRENGRANSHIMUQIANNASHZHENDUANDE“JINBIAOZHUN”。ZAINASH YAOWUYANFAZHONG,GANZUZHIBINGLIXUESHIQUEZHENGXINGLINCHUANGSHIYANZHONGSHOUSHIZHEZHENDUANJIZHUYAOZHONGDIANDEPINGJIAZHIBIAO。NAFLD/NASHDEZUZHIXUEPINGJIAXITONGZHUYAOBAOKUO BruntXITONG、MEIGUONASHLINCHUANGYANJIUWANGLUOPINGFENXITONG(NASH-CRN)、OUZHOUZHIFANGGANJINZHANZUDUANZUZHIXUEPINGFENXITONG(Fatty Liver Inhibition of Progression,FLIP-SAF)DENG。

  GULITANSUOWUCHUANGBIAOZHIWUZUOWEIZAOQICHUBUSHAIXUANNASHSHOUSHIZHEDEFANGFA,QIZHONGBAOKUOALTDENGXUEQINGSHENGHUAZHIBIAOHEFUBUCHAOSHENG、HECIGONGZHENCHENGXIANGDENGYINGXIANGXUEZHIBIAO。

  2.ZHONGDIANZHIBIAOPINGJIA

  YOUXIAOXINGPINGJIAZHONGDIANBAOKUOLINCHUANGJIEJUZHONGDIANHEGANZUZHIXUETIDAIZHONGDIAN,YIJIXUEQINGSHENGHUAJIANCHA、YINGXIANGXUEJIANCHADENGQITATANSUOXINGZHONGDIAN。

  (1)LINCHUANGJIEJUPINGJIA

  DUIYUNASHWUGANYINGHUADEHUANZHE,LINCHUANGZHONGDIANBAOKUOJINZHANZHIGANYINGHUA、CHUXIANSHIDAICHANGSHIJIAN(FUSHUI、SHIGUANWEIDIJINGMAIQUZHANGCHUXUEHUOGANXINGNAOBINGDENG)、GANYIZHI、GANXIBAOAIHUOGANBINGXIANGGUANSIWANG/QUANYINSIWANGDENGSHIJIAN。

  DUIYUNASHGANYINGHUADAICHANGQIDEHUANZHE,LINCHUANGZHONGDIANBAOKUOCHUXIANSHIDAICHANGSHIJIAN、GANYIZHI、GANXIBAOAIHUOGANBINGXIANGGUANSIWANG/QUANYINSIWANGDENGSHIJIAN。

  (2)GANZUZHIBINGLIXUEPINGJIA

  GANZUZHIBINGLIXUEPINGJIAZHIBIAOBAOKUOZHIFANGXINGGANYAN、XIANWEIHUADEGAISHAN。

  ZUZHIBINGLIXUEPINGJIAZHILIANGSHOUDUOZHONGYINSUYINGXIANG,BAOKUOHUOJIANFANGSHI、HUOJIANLEIXING(CUZHENCHUANCI/XIEXINGHUOJIAN)、CHUANCIBUWEI、CHUANCIZHENGUIGEYIJIBINGLIXUEZHUANJIAPINGGUDENG。WEIBAOZHENGZUZHIXUEYANGBENDECHULIZHILIANG,YAOQIUYANGEZUNXUNBINGLIYANGBENSOP(Standard Operation Procedure)。WEIJIANSHAOZUZHIBINGLIXUEPINGJIADECHAYI,BINGLIDUPIANYINGCAIYONGZHONGXINYUEPIAN,JIANYIYOULIANGMINGJIYISHANGGANZANGBINGLIZHUANJIAJINXINGSHUANGMANGDUPIAN。GANZUZHIBINGLIXUEYANGBENSOPKECANKAOXIANGGUANZHIDAOYUANZE,RU:《GANXIANWEIHUAZHENDUANJIZHILIAOGONGSHI》DENG。

  (3)YINGXIANGXUEPINGJIA

  CIGONGZHENZHIZIMIDUZHIFANGFENSHU(Magnetic Resonance Imaging–derived Proton Density Fat Fraction,MRI-PDFF)KEDINGLIANGPINGJIAGANZANGZHIFANGHANLIANG。ZAIPEIXUNHELIANGHAOZHIKONGDEQIANTIXIA,KEYIYONGMRI-PDFFGAIBIANDEJUEDUIZHIHUOZHEXIANGDUIBAIFENBIPINGJIAYIGANZHIFANGBIANWEIZHILIAOBADIANDEYAOWU。

  CIGONGZHENDANXINGCHENGXIANG(Magnetic Resonance Elastography,MRE)HESHUNSHIDANXINGCHENGXIANG(Transient Elastography,TE)DENGWUCHUANGJISHUKEYIYONGYUPINGJIAGANXIANWEIHUAGAIBIAN。QIZHONGTETONGSHILIANHEJIANCEKONGZHISHUAIJIANCANSHU(Controlled Attenuation Parameter,CAP)KEYIXIEZHUPINGJIAGANZHIFANGBIAN。DANSHIYOUYUSHOUDAOGANZANGYANZHENG、DANZHIYUJI、CAOZUOGUIFANDENGYINSUYINGXIANG,ZAIZHENDUANNASHXIANWEIHUACHENGDUHEPANDUANZHILIAOQIANHOULIAOXIAOFANGMIAN,RENGBUNENGTIDAIZUZHIBINGLIXUEPINGJIA。

  (4)XUEQINGXUEPINGJIA

  WUCHUANGZHIBIAOZHONG,YUPINGJIATANGZHIDAIXIEXIANGGUANDEYOUTIZHONG、TIZHILIANGZHISHU(BMI)、YAOTUNBI、KONGFUXUETANG、TANGHUAXUEHONGDANBAI、YIDAOSUDIKANG(RUHOMA-IR)、XUEZHIDENG。YUGANZANGYANZHENG/SUNSHANGXIANGGUANDEYOUALT、AST、CK18PIANDUANDENG。YUPINGJIAGANXIANWEIHUAXIANGGUANDEYOUFibro Test、ELF(Enhanced Liver Fibrosis)、NAFLDXIANWEIHUAPINGFEN(NAFLD Fibrosis Score,NFS)、Pro-C3、FIB-4、ASTYUPLTBIZHIZHISHU (AST/PLT Ratio Index,APRI)DENG。

  (5)QITA

  YONGYUPINGJIAGANYINGHUALINCHUANGJIEJUDEZHIBIAOBAOKUOGANJINGMAIYALITIDU(Hepatic Venous Pressure Gradient,HVPG)HEGANGONGNENGChild-PughPINGFEN、ZHONGMOQIGANBINGMOXING(Model for End-stage Liver Disease,MELD)PINGFENDEBIANHUA。

  3.FANGFAXUEKAOLV

  JIJIESHOUCHUANTONGDELINCHUANGYANFASHEJI,YEJIESHOUXINYINGSHEJI,RU:SHIYINGXINGSHEJIDENG,DANYINGZAIFANGANZHONGSHIXIANSHUOMING。RUCAIYONGXINYINGSHEJI,JIANYIYUYAOPINJIANDUGUANLIBUMENSHIXIANGOUTONG。

  SUIJIFENZUSHIKEYIKAOLVCAIYONGFENCENGSUIJIHUADEFANGFA,RU:KAOLVTANGNIAOBINGDENGBINGCUNJIBINGYINSU。

  YINGGAITIGONGMINGQUEZHENGJUZHENGMINGHUANZHEZAISUIJIRUZUQIAN6~8ZHOUTIZHONGHEDAIXIECANSHUBAOCHIWENDING。WENDINGDETIZHONGDINGYIWEIBIANHUABUCHAOGUO5%。

  JIANYIBIMIANSHIYONGKENENGYINGXIANGLIAOXIAOPINGJIADEHEBINGYONGYAO,RUGUOSHIYONG,JIANYIZHISHAOYOU3GEYUEDEWENDINGJILIANG。

  RUYANJIUZHONGSHEJIDUOGEYAOWUDUOBADIANLIANHEZHILIAOHUOGUDINGJILIANGFUFANGZHIJI,XUYAOTIGONGLIANHEYONGYAODECHONGFENYIJU。

  RUYANJIUZHONGSHEJIHEBINGYONGYAO,BAOKUOZHONGYAODENG,XUYAOZAIYANJIUFANGANZHONGMINGQUEGUIDING,BINGXIANGXIJILUXIANGGUANXINXI。

  ZAIGUOJIDUOZHONGXINLINCHUANGSHIYANZHONG,YINNASHYUYINSHIDENGSHENGHUOFANGSHIJIYICHUANDAIXIEYINSUXIANGGUAN,YINGGUANZHUZHONGZUCHAYI(BAOKUOLINCHUANGYAOLIXUEHELINCHUANGSHIJIANFANGMIANDECHAYI)。JIANYIZAIZAOQIJIEDUANJIARUQUANQIUYANFA,YIBAOZHENGSHOUSHIZHENENGGOUCHONGFENDAIBIAOZHONGGUORENQUN。

  (ER)BUTONGYANFAJIEDUANJUTIKAOLV

  1.LINCHUANGYAOLIXUEYANJIU

  TONGCHANG,LINCHUANGYAOLIXUEYANJIUBAOKUORENTINAISHOUXINGSHIYAN、RENTIYAODAIDONGLIXUEHEYAODONGXUE/YAOXIAOXUESHIYAN。

  YOUYUZHILIAONASHDEYAOWUDUOXUJIAOZHANGSHIJIANJIYAO,YINCI,CHUFEISHOUYAOWUDEDUXINGHUOYAOLIZUOYONGSUOJINJI,ZAIDUOCIJIYAONAISHOUXINGSHIYANZHONGJIYAODESHIJIANYINGZUGOUZHANG。

  DUIYUKENENGSHEJIDAOGANZANGDAIXIEDEYAOWU,ZAIZAOQIYANFAJIEDUANYINGKAIZHANGANGONGNENGSUNHAIDUIYAOWUYAODAIDONGLIXUEDEYINGXIANGYANJIU,WEIHOUXULINCHUANGSHIYANZHONGHELIDEJIYAOFANGANJIJILIANGDIAOZHENGTIGONGZHICHI。

  ZAIYAOWUDEZAOQIYANFAJIEDUAN,KEYIKAOLVYIYINGXIANGXUE、XUEQINGXUE、NASHGANXIANWEIHUAWUCHUANGPANBIEMOXINGDENGZUOWEIYAOXIAOXUEZHIBIAO,JINXINGXIAOYANGBEN、DUANLIAOCHENGDEYAODONGXUE/YAOXIAOXUEPINGGU,QUANMIANLEJIEYAOWUDEBAOLU/XIAOYINGZUOYONGTEDIAN,WEIHOUXULINCHUANGSHIYANTIGONGZHIDAO。

  ZAOQIYANFAJIEDUANYINGZHENDUIYAOWUTINEICHUZHIGUOCHENGGUANJIANHUANJIE,RUGUANJIANDAIXIEMEIHUOZHUANYUNTIDEDIWU、YOUDAOJIHUOYIZHIJIDENG,KAIZHANYAOWUXIANGHUZUOYONGYANJIU。NASHHUANZHECHANGTONGSHIHEBINGTANGNIAOBING、GAOXUEYA、GAOZHIXUEZHENG、TONGFENGDENGDAIXIEXIANGGUANJIBING,ERQIE,CILEIHUANZHEDEXINNAOXUEGUANSHIJIANFENGXIANZENGJIA。YINGZHONGDIANGUANZHUYUYISHANGJIBINGCHANGYONGYAOWUHEBINGYONGYAODEYAOWUXIANGHUZUOYONG。JIYUQUNTIYAODAIDONGLIXUEFENXIYEYOUZHUYUMIAOSHUYIZHIHUOXINQUEDINGXIANGHUZUOYONGDELINCHUANGYINGXIANG,BINGTIGONGJILIANGDIAOZHENGDEJIANYI。

  2.TANSUOXINGLINCHUANGSHIYAN

  (1)ZAOQIGAINIANYANZHENG

  NASHYAOWUDEZAOQIGAINIANYANZHENGYINGFUHEGAIQIDEYIBANYUANZE。TIGONGCHUBUDEZHENGJUZHICHIHOUXUDELINCHUANGSHIYAN,BAOKUORUZUBIAOZHUN、LINCHUANGSHIYANDEZHOUQIYIJIZHONGDIANDESHEZHI。

  SHOUSHIZHEDERUXUANKECAIYONGXUEQINGSHENGHUAJIANCHAHUOYINGXIANGXUEFANGFA。

  ZHUYAOLIAOXIAOZHIBIAOKECAIYONGWUCHUANGXINGBIAOZHIWU,BAOKUOMRI-PDFF、MREDENGYINGXIANGXUEGAIBIAN,YIJIGANZANGJIBINGTEYIXINGDEXUEQINGSHENGHUAZHIBIAODEBIANHUADENG,YEKEJIEHEZUZHIBINGLIXUE、YINGXIANGXUEHEXUEQINGSHENGHUAJIANCHADENGWUCHUANGBIAOZHIWUDEBIANHUAGONGTONGPINGJIAGANZANGZHIFANGHANLIANG、YANZHENGHEXIANWEIHUA。

  JIYAOJILIANGHEZHILIAOCHIXUSHIJIANYAOGENJUZUOYONGJIZHIJIDUIYUSUOXUANLIAOXIAOZHIBIAODEYUQIZUOYONGLAISHEJI,YINGYOUZUGOUZHANGDEZHONGDIANGUANCHASHIJIAN。JIANYIGAIJIEDUANTANSUODUOGEJILIANGZUOWEIHOUXUSHEJIDEXUANZE。

  (2)HOUQITANSUO

  SHEJI:ANWEIJIDUIZHAO、SUIJI、SHUANGMANGSHEJI。

  SHOUSHIZHE:RUXUANXUKAOLVNIANLING、XINGBIE、ZHENDUANBIAOZHUN、JIBINGYANZHONGCHENGDU、HEBINGJIBINGDENG。JIANYINARUJINGGANZUZHIBINGLIXUEQUEZHENDENASHHUANZHE,GANZUZHIHUOJIANZHIRUZUDESHIJIANCHUANGYIBANBUCHAOGUO6GEYUE,ZAIGAISHIJIANCHUANGNEIXUZHUYIHUANZHESHIFOUJIESHOUKENENGYINGXIANGGANZUZHIXUEBIANHUADEGANYU。DUIYUNASHWUGANYINGHUADEHUANZHE,MUQIANJIANYIDEZHUYAORUZUBIAOZHUN:NASPINGFEN≥4FEN,QIZHONGYANZHENGHEQIQIUYANGBIANGEZHISHAO1FEN;TONGSHI,F2≤CRNXIANWEIHUA12FEN,CTPPINGFEN>6FEN,HEBINGQITAGANZANGJIBINGDENASH。

  ZHUYAOLIAOXIAOZHIBIAO:

  YIZUZHIXUEGAISHANWEIZHUYAOLIAOXIAOZHIBIAOSHI,TUIJIAN:①NASHGAISHAN,TONGSHIXIANWEIHUAWUEHUA;HUOZHE,②GANZUZHIXIANWEIHUAGAISHAN1FENJIYISHANG,TONGSHINASHWUEHUA;HUOZHE,③NASHGAISHANTONGSHIGANZUZHIXIANWEIHUAGAISHAN1FENJIYISHANG。NASHGAISHANDINGYIWEINASPINGFENZHISHAOJIANGDI2FEN,QIZHONGQIQIUYANGBIANZHISHAOJIANGDI1FEN,ZHIFANGBIANPINGFENBUZENGJIA。NASHWUEHUADINGYIWEIZAINASPINGFENZHONGDEYANZHENG、QIQIUYANGBIANHEZHIFANGBIANPINGFENJUNBUZENGJIA。

  DUIYUNASHGANYINGHUADAICHANGQIDEHUANZHE,YEKEYIXUANZELINCHUANGJIEJUZHONGDIANZUOWEIZHUYAOLIAOXIAOZHIBIAO。

  JIYAOJILIANGHEZHILIAOCHIXUSHIJIAN:KESHEZHIDUOGEJILIANGZU,PINGJIAYAOWUDELIANGXIAOGUANXI。YINGBAOZHENGZUGOUZHANGDEYANJIUSHIJIANYIGUANCHAZUZHIXUEGAISHAN,ZHISHAOYAODADAO12~18YUE。

  3.QUEZHENGXINGLINCHUANGSHIYAN

  SHEJI:ANWEIJIDUIZHAO、SUIJI、SHUANGMANGSHEJI。

  SHOUSHIZHE、JIYAOJILIANGHEZHILIAOCHIXUSHIJIANTONGHOUQITANSUOXINGLINCHUANGSHIYAN。

  ZHUYAOLIAOXIAOZHIBIAO:

  DUIYUNASHWUGANYINGHUADEHUANZHE,MUQIANKEJIESHOUDEGANZUZHIBINGLIXUETIDAIZHONGDIANBAOKUOZHIFANGXINGGANYANHE/HUOXIANWEIHUADEGAISHAN。

  DUIYUNASHGANYINGHUADAICHANGQIDEHUANZHE,RUGUOXUANZEGANZUZHIBINGLIXUEZUOWEITIDAIZHONGDIAN,YINGYOUCHONGFENDEKEXUEYIJU,BINGSHIXIANYUYAOPINJIANDUGUANLIBUMENJINXINGGOUTONG。

  YIZUZHIXUEGAISHANWEIZHUYAOLIAOXIAOZHIBIAOSHI,TUIJIAN:①NASHHUANJIETONGSHI,XIANWEIHUAWUEHUA;HUOZHE,②GANZUZHIXIANWEIHUAGAISHAN1FENJIYISHANG,TONGSHINASHWUEHUA;HUOZHE,③NASHHUANJIETONGSHIGANZUZHIXIANWEIHUAGAISHAN1FENJIYISHANG。NASHHUANJIEDINGYIWEINASPINGFENZHONGYANZHENGPINGFENWEI0-1FEN,QIQIUYANGBIANPINGFENWEI0FEN,ZHIFANGBIANPINGFENBUZENGJIA。NASHWUEHUADINGYIWEIZAINASPINGFENZHONGDEYANZHENG、QIQIUYANGBIANHEZHIFANGBIANPINGFENJUNBUZENGJIA。

  YOUYUNASHDEZHILIAOKENENGXUYAOZHANGQIFUYAO,YINGKAOLVTINGYAOHOUSUIFANG。

  ZAIQUEZHENGXINGLINCHUANGSHIYANTONGSHIKEJINXINGQUNTIYAODAIDONGLIXUEYANJIU、YAOWUJIYINZUXUEYANJIUDENG。

  4.QUEZHENGLINCHUANGHUOYIDESHIYAN

  JIANYUZUZHIXUEGAISHANDETIDAIZHONGDIANYULINCHUANGJIEJUDEXIANGGUANXINGSHANGWEIQUELI,YINGJINXINGLINCHUANGSHIYANQUEZHENGLINCHUANGJIEJUDEHUOYI。

  TUIJIANYIXIAFUHEZHONGDIAN:CHUXIANSHIDAICHANGSHIJIAN(FUSHUI、SHIGUANWEIDIJINGMAIQUZHANGCHUXUEHUOGANXINGNAOBING)、GANYIZHI、MELDPINGFEN≥15、GANXIBAOAI、QUANYINSIWANG。DUIYUNASHWUGANYINGHUADEHUANZHE,HAIBAOKUOJINZHANZHIGANYINGHUA。

  (SAN)ANQUANXINGPINGJIA

  YOUYUNASHXUYAOZHANGSHIJIANDELIANXUFUYAO,YINCIXUYAOYOUZUGOUDEBAOLULIANGHEBAOLUSHIJIANJINXINGANQUANXINGGUANCHA。JIANYIZAIZHANGQISHIYANZHONGSHELIDULIDEKEXUEWEIYUANHUI。

  NASHLINCHUANGSHIYANZHONGYINGTEBIEGUANZHUYIXIAKENENGDEBULIANGSHIJIAN:

  1.GANZANGBULIANGSHIJIAN:YOUYUNASHHUANZHEDUIYAOWUSUOZHIDEGANSUNSHANGMINGANXINGZENGJIA,YOUSHIYAOWUKENENGYOUFAGANSUNSHANGJIAZHONG,SHEJILINCHUANGSHIYANSHIYINGJIANGZHEIYIKENENGXINGKAOLVZAINEI。YINGJINLIANGQUEDINGGANSUNSHANGJIAZHONGDEYUANYIN,HAIYINGTEBIEGUANZHUTINGYAOHOUFANTIAOXINGGANGONGNENGYICHANG。DUIYUYOUQIANZAIGANZANGDUXINGDEYAOWU,YINGZAILINCHUANGSHIYANZHONGSHELIJIANCEJIHUA。

  2.SHENZANGBULIANGSHIJIAN:YOUYUNASHBENSHENHUIZENGJIAMANXINGSHENZANGJIBINGDEFENGXIAN,ZAISHIYANQIANHESHIYANGUOCHENGZHONGYAOQUANMIANPINGGUHEJIANCESHOUSHIZHEDESHENZANGGONGNENG。

  3.XINXUEGUANBULIANGSHIJIAN:XINXUEGUANSHIJIANSHINASHHUANZHEDEZHUYAOSIYIN,YINGGENJUYAOWUDETEDIAN,JIANCEYAOWUDUIXINXUEGUANXITONGDEYINGXIANG。

  4.DAIXIEHENEIFENMIBULIANGSHIJIAN:NASHCHANGHEBINGDAIXIEZONGHEZHENG,YINGGENJUYAOWUDETEDIAN,JIANCEDUITIZHONG、XUETANGDENGDAIXIEZHIBIAODEYINGXIANG。

  四、参考文献

  1.FEIJIUJINGXINGZHIFANGXINGGANBINGZHENLIAOFANGZHIZHINAN(2018GENGXINBAN).ZHONGHUAGANZANGBINGZAZHI,2018,26(3):195-203.

  2.GANXIANWEIHUAZHENDUANJIZHILIAOGONGSHI(2019NIAN).LINCHUANGGANDANBINGZAZHI,2019,35(10):2163-2172.

  3.NMPA.YAOWULINCHUANGSHIYANDEYIBANKAOLVZHIDAOYUANZE.2017NIAN1YUE

  4.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.

  5.Angulo P, Kleiner DE, Dam-Larsen S,et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease [J]. Gastroenterology, 2015,149:389–397.

  6.Younossi ZM,Koenig AB,Abdelatif D,et al. Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence,incidence,and outcome [J].Hepatology,2016,64(1):73-84.

  7.Sanyal AJ,Miller V. Regulatory science and drug approval for alcoholic and nonalcoholic steatohepatitis [J]. Gastroenterology, 2016,150(8):1723–1727.

  8.Hannah WN, Torres DM, Harrison SA. Nonalcoholic steatohepatitis and endpoints in clinical trials [J]. Gastroenterology & Hepatology,2016,12(12):756-763.

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