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Volume 39 Issue 3
May  2021
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JIN Jiangwei, SHI Jianrong, CAI Jian, LI Guihua, LU Saihua, XU Feng. Quality evaluation of clinical trial literatures on the COVID-19 treatment with traditional Chinese medicine (TCM)[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(3): 206-210. doi: 10.12206/j.issn.1006-0111.202012012
Citation: JIN Jiangwei, SHI Jianrong, CAI Jian, LI Guihua, LU Saihua, XU Feng. Quality evaluation of clinical trial literatures on the COVID-19 treatment with traditional Chinese medicine (TCM)[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(3): 206-210. doi: 10.12206/j.issn.1006-0111.202012012

Quality evaluation of clinical trial literatures on the COVID-19 treatment with traditional Chinese medicine (TCM)

doi: 10.12206/j.issn.1006-0111.202012012
  • Received Date: 2020-12-08
  • Rev Recd Date: 2021-05-15
  • Available Online: 2021-05-25
  • Publish Date: 2021-05-25
  •   Objective  To evaluate the quality of the clinical trial literatures published on the treatment of COVID-19 with TCM, find out the shortcomings and put forward corresponding suggestions, in order to promote TCM against COVID-19.  Methods  "COVID-19", "New Coronavirus Pneumonia", "TCM", "Chinese Medicine", "Clinical Trial", "Lianhua Qingwen", "Huoxiang Zhengqi", "Jinhua Qinggan", and other keywords were used to search relevant literatures in CNKI and PubMed database. Among the all the screened relevant literatures on the treatment of COVID-19 with TCM, the literature quality was assessed according to evaluation criteria of clinical trial literatures.  Results  A total of 463 papers related to the treatment of COVID-19 with TCM were obtained. 440 papers on theoretical research on the network pharmacology mechanism of Chinese medicine treatment of COVID-19 were excluded. Among the 23 articles included in the quality analysis, there are 3 randomized controlled studies, 1 multi-center prospective randomized controlled trial, 2 disease case report trials, and 5 uncontrolled single arm studies, 5 controlled trials and 7 retrospective studies. In the period of more than half a year, although many clinical trial documents of TCM for the treatment of COVID-19 have been published, the clinical trial design reflected in most TCM clinical trials were not standardized. There are problems in "randomness and rationality", such as no control group, no randomization design, only case studies, no blinding method in controlling bias, and insufficient objectivity in the evaluation criteria of efficacy. All of these need to be improved.  Conclusion  The treatment of new coronavirus pneumonia with TCM still requires more and standardized clinical trial verifications and publications to generate strong evidence-based results, such as adding control groups, increasing sample size, and using blinding methods to increase the credibility of clinical trials.
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Quality evaluation of clinical trial literatures on the COVID-19 treatment with traditional Chinese medicine (TCM)

doi: 10.12206/j.issn.1006-0111.202012012

Abstract:   Objective  To evaluate the quality of the clinical trial literatures published on the treatment of COVID-19 with TCM, find out the shortcomings and put forward corresponding suggestions, in order to promote TCM against COVID-19.  Methods  "COVID-19", "New Coronavirus Pneumonia", "TCM", "Chinese Medicine", "Clinical Trial", "Lianhua Qingwen", "Huoxiang Zhengqi", "Jinhua Qinggan", and other keywords were used to search relevant literatures in CNKI and PubMed database. Among the all the screened relevant literatures on the treatment of COVID-19 with TCM, the literature quality was assessed according to evaluation criteria of clinical trial literatures.  Results  A total of 463 papers related to the treatment of COVID-19 with TCM were obtained. 440 papers on theoretical research on the network pharmacology mechanism of Chinese medicine treatment of COVID-19 were excluded. Among the 23 articles included in the quality analysis, there are 3 randomized controlled studies, 1 multi-center prospective randomized controlled trial, 2 disease case report trials, and 5 uncontrolled single arm studies, 5 controlled trials and 7 retrospective studies. In the period of more than half a year, although many clinical trial documents of TCM for the treatment of COVID-19 have been published, the clinical trial design reflected in most TCM clinical trials were not standardized. There are problems in "randomness and rationality", such as no control group, no randomization design, only case studies, no blinding method in controlling bias, and insufficient objectivity in the evaluation criteria of efficacy. All of these need to be improved.  Conclusion  The treatment of new coronavirus pneumonia with TCM still requires more and standardized clinical trial verifications and publications to generate strong evidence-based results, such as adding control groups, increasing sample size, and using blinding methods to increase the credibility of clinical trials.

JIN Jiangwei, SHI Jianrong, CAI Jian, LI Guihua, LU Saihua, XU Feng. Quality evaluation of clinical trial literatures on the COVID-19 treatment with traditional Chinese medicine (TCM)[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(3): 206-210. doi: 10.12206/j.issn.1006-0111.202012012
Citation: JIN Jiangwei, SHI Jianrong, CAI Jian, LI Guihua, LU Saihua, XU Feng. Quality evaluation of clinical trial literatures on the COVID-19 treatment with traditional Chinese medicine (TCM)[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(3): 206-210. doi: 10.12206/j.issn.1006-0111.202012012
  • 目前,全球正在奋力抗击新冠肺炎(COVID-19)疫情,中国成功地控制了疫情的传播,并对新冠肺炎患者开展了有效的治疗。其中,中医药对COVID-19患者发挥了整体调节、提高免疫、激发自身抗病能力和康复能力等功效,为疫情防控做出了重要贡献。中西医结合、中西药并用是防治COVID-19疫情的一大特点,也是中医药传承精华、守正创新的生动实践,诸多相关临床研究成果也形成了很多论文在国内外发表。然而,限于疫情控制时间紧迫和临床试验设计过于仓促,其中有些临床研究论文还不够成熟,尚未形成坚实有力的循证医学证据。笔者拟从中药治疗新肺炎的文献质量评价着手,分析探讨可能存在的中药治疗新冠肺炎的研究试验设计问题,并提出改进意见。

  • 在中国知网(https://www.cnki.net/),PubMed数据库(https://pubmed.ncbi.nlm.nih.gov/),以“COVID-19” “新冠病毒肺炎” “TCM” “中医药” “Clinical trial ”“临床试验” “连花清瘟” “Lianhua Qingwen” “藿香正气” “Huoxiang Zhengqi” “金花清感” “Jinhua Qinggan ” “清肺排毒” “Qing Fei Pai Du”等作为关键词,搜索以中药方剂、中成药、协定方等中药颗粒或胶囊治疗新冠肺炎的临床试验文献,检索时间截至2020年12月31日0时。剔除网络药理学理论研究、中药抗病毒分子机制研究、中医药组方理论研究等与临床试验无关的文献。

  • 运用Excel 2020逐个录入检索数据,内容包括:①论文的基本信息,包括论文题目、作者、单位、期刊名、发表时间等;②临床试验所采用的试验方法;③试验样本量、疗效等指标。

  • 截至2020年12月31日,共获得初始文献463篇,逐篇查看论文内容后,剔除网络药理学机制研究或理论研究论文441篇,获得22篇中医药治疗新冠肺炎的临床试验文献纳入分析。

  • 在所选中的22篇中药治疗新冠病毒肺炎临床试验论文中,有1篇文献报告采用了前瞻性多中心研究,有3篇文献报告采用了随机对照的方法,7篇文献采用了回顾性研究方法,4篇文献报告采用了对照试验,2篇文献为病例报告,5篇文献报告采用了单臂研究。

    临床试验的样本量是评价试验质量的一个重要指标,从表1中可以看到22篇临床试验中,样本量大于100的仅有9篇文献,其余多为小样本量临床试验(小样本量通常指样本量小于200)。有2篇仅为病例报告。按临床试验文献评价标准[1]:一级为随机对照、前瞻性研究、中药单用;二级为对照试验、回顾性研究、中药单用;三级为单臂研究(w/t ctrl);四级为病例报告。22篇文献按此标准仅4篇评为一级,11篇评为二级,5篇评为三级,2篇评为四级(表1)。

    第一作者药物干预措施样本量评价等级
    程德忠[2]连花清瘟胶囊102二级
    段璨[3]金花清感联合西药123二级
    吕睿冰[4]连花清瘟胶囊联合西药101二级
    倪受东[5]清肺排毒汤1四级
    张丽[6]连花清瘟胶囊1四级
    杨焕彪[7]藿香正气散联合西药11三级
    柳丽丽[8]连花清瘟胶囊联合阿尔比多32二级
    Hu K[9]连花清瘟胶囊284一级
    程德忠[10]连花清瘟胶囊54三级
    Liu ZL[11]金花清感胶囊80二级
    Xiao MZ[12]藿香正气与连花清瘟胶囊283一级
    姚开涛[13]连花清瘟胶囊联合西药42二级
    谢鑫[14]柴胡甘露饮46三级
    连捷[15]中药汤剂联合西药64二级
    刘俊[16]中西药联合治疗22二级
    李旷宇[17]清肺排毒汤联合西药60二级
    董丽[18]清肺排毒汤联合西药2三级
    孟军华[19]清肺排毒汤108二级
    余平[20]连花清瘟胶囊联合阿尔比多295一级
    孙易娜[21]清肺排毒汤295二级
    巴元明[22]“肺炎一号”联合西药451三级
    史锁芳[23]益气养阴颗粒联合促康复功法90一级
  • 22篇临床试验文献中,6篇报道了治愈率,4篇报道了转重症率。轻症患者仅表现低热、轻微乏力,无肺炎表现,而重症则表现为呼吸困难和/或低氧血症,严重者可快速进展为急性呼吸窘迫综合征、脓毒症休克、难以纠正的代谢性酸中毒和出现凝血功能障碍及多器官功能衰竭等[24]。从表1数据可以看出,使用中药联合西药常规治疗后,试验组的治愈率明显高于对照组,转重症率也明显低于对照组。可见中药能够有效提高治愈率,改善新冠肺炎的治疗结局(表2)。

    药物干预治疗时间
    t/d)
    治愈率(%) 转重症率(%)
    试验组对照组试验组对照组
    连花清瘟胶囊786.368.67.821.6
    连花清瘟胶囊联合西药10n/an/a6.415.8
    藿香正气散联合西药n/a100w/t ctrl9.1w/t ctrl
    连花清瘟胶囊1478.966.2n/an/a
    清肺排毒汤联合西药n/a90.080.3n/an/a
    清肺排毒汤n/a97.673.1n/an/a
    中药汤剂联合西药n/an/an/a011.5
    金花清感胶囊n/a45.527.8n/an/a
    注:n/a表示未提及;w/t ctrl表示无对照。
  • 在22篇临床试验文献中,有6篇文献报告了主要症状的消失率,结果显示中药单用或联合西药在改善发热、咳嗽以及乏力症状等方面均优于对照组,在新冠肺炎治疗中,中药的整体调节功能发挥了作用(表3)。

    药物干预治疗时间(t/d)发热咳嗽乏力
    试验组对照组试验组对照组试验组对照组
    连花清瘟胶囊联合西药1086.766.755.630.682.558.6
    连花清瘟胶囊联合西药n/a85.757.146.75.641.730.8
    连花清瘟胶囊783.761.062.235.961.334.3
    藿香正气散联合西药n/a100w/t ctrl60w/t ctrl100w/t ctrl
    金花清感颗粒联合西药580.353.166.142.977.653.8
    连花清瘟胶囊780.0w/t ctrl75.7w/t ctrl76.7w/t ctrl
    注:n/a表示未提及;w/t ctrl表示无对照。
  • 在22篇临床试验文献中,有4篇文献报告了其他症状和体征的消失率,结果显示中药干预在气促、胸闷、湿啰音、呼吸困难症状的改善方面优于对照组(表4)。

    药物干预治疗时间(t/d)气促 湿啰音 胸闷 呼吸困难
    试验组对照组试验组对照组试验组对照组试验组对照组
    连花清瘟胶囊联合西药1068.220.0 56.020.0 70.863.2 50.011.1
    连花清瘟胶囊联合西药n/a77.80n/an/a71.422.250.050.0
    连花清瘟胶囊761.514.3n/an/a54.615.866.728.6
    连花清瘟胶囊7n/an/a89.5w/t ctrl84.6w/t ctrl100w/t ctrl
    注:n/a表示未提及;w/t ctrl表示无对照。
  • 22篇临床试验文献中,涉及中药复方制剂的有连花清瘟、金花清感、藿香正气、清肺排毒汤、柴胡饮甘露、清肺排毒汤、肺炎一号、益气养阴颗粒,结果显示患者均无不良反应。

  • 新冠病毒肺炎疫情迄今仍未得到有效控制,亦无特异性药物治疗[25-27]。目前,国外疫情仍有蔓延态势,确诊人数每天都在增加。在我国,新冠肺炎疫情已经得到了非常有效的控制,中医药干预功不可没。

    历史悠久的传统中医药之所以能够发展传承至今,可能与其对疾病的有效防治以及对机体的调理作用有关。在本次对抗COVID-19的防治中,中医药以其独特的理论体系以及治疗理念,显示出其特有的功效。然而,也正是由于暂时还无法用现代医学的理论体系解释,所以很难得到大众的认可。比如,在WHO提供的《2019冠状病毒病临床管理》临时文件中(在线版),有关治疗方案仍然只谈化学药物治疗预防,对于中医药只字未提,可见在国际上化学药物依旧是治疗新冠肺炎的主力药。

    中医药治疗新型冠状肺炎的成效尚未得到国际的承认,部分原因可能在于:中药采用的是个体化治疗,每一个病例采用的药材、组方、剂量都可能会因人而异,不像现代药物为标准化大规模生产供应和临床应用;中药尤其是一些复方制剂,其内在成分非常复杂,有的还无法明确地阐明药理作用机制以及作用靶点等。所以中药想要得到进一步的推广使用,需要以当前国际公认的药物评判标准去衡量,为它提供更强有力的证据。从这个角度来看,我们收集到22篇临床试验文献所采用的研究方法多为回顾性研究以及单臂研究,循证医学证据力度不够。

    纵观近20年我国中药临床试验研究历史,虽然项目数量快速增长,但临床研究依旧存在不少的缺陷,如研究与方法设计质量较低、使用的随机方法不当、试验样本量过低、观察指标的不准确和不规范,并且缺乏长期跟进的指标,这些指标都会在一定程度上影响数据的可靠性,研究结论往往难以得到国际的认可。随机对照试验是当前国际上公认的一种方法,而上述22项研究中仅有4项为随机对照。临床随机对照试验是将试验群体进行随机化的分组,其主要目的便是减少人为选择所导致的偏倚性,使得两组或多组的试验对象在特征上尽量做到相似。随机对照能够使试验数据更真实、更具有说服力。一项临床试验如果由一位临床医师亲自设计,然后亲自对患者进行随机分组,则无法称之为随机对照,而只能说是开放性试验,要想真正做到随机化,可尝试采取计算机产生随机数字进行对照与试验的分组。没有进行恰当隐藏的随机对照试验可能会过分夸大疗效30%~50%[28]。所以,唯有将随机对照贯彻落实,进行恰当隐藏,方能得到更加真实的数据,中药治疗新冠肺炎的临床试验仍需做更多、更好的随机对照试验,才能更好地证明其疗效。

    临床试验中是否使用盲法也是评价一个临床试验优与劣的重要指标。采用了双盲法的临床试验对于未使用盲法的试验,后者会夸大15%左右的疗效[29],从而导致试验结果失真。使用盲法试验能够有效避免试验对象以及试验人员的主观偏向,从而导致试验结果产生偏倚。而在上述22篇临床试验文献中,基本并未使用盲法试验,试验结论难以令人信服。

    临床试验的研究报告中,样本量是一项重要指标。理论上来说研究某一试验,其对照组与试验组的样本量越大,试验结果便越接近于真值。但由于资源、患者人数的种种限制,试验的样本量自然也是无法做到无穷大,因此,在做临床试验的研究应当制定符合统计学检验要求的恰当的样本量,试验时需在患者人群中选取具有代表性的。而在上述22篇临床试验文献中,基本为小样本试验。要想将中药治疗新冠肺炎的疗效推广,亟需做更多大样本量的临床试验。

  • 在抗击新冠肺炎疫情中,中药联合西药治疗,提高了治愈率,改善了临床症状,发挥了重要作用。但已有的临床试验文献仍存有许多不足。循证医学强调一切以高质量的证据说话,中医药想要在国际获得推广应用,需要借助现代循证医学提供坚实有力的医学证据。前瞻性、多中心(大样本)、双盲随机对照试验才是未来的方向,而中医药需向这些金指标迈进。

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