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氯喹和洛匹那韦/利托那韦片治疗轻/普通型新型冠状病毒(CoVID-19)感染者的疗效研究:一项前瞻性、开放性、多中心随机对照临床研究
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注册号:

Registration number:

ChiCTR2000029741 

最近更新日期:

Date of Last Refreshed on:

2020-02-13 

注册时间:

Date of Registration:

2020-02-11 

注册号状态:

预注册  

Registration Status:

Prospective registration  

注册题目:

氯喹和洛匹那韦/利托那韦片治疗轻/普通型新型冠状病毒(CoVID-19)感染者的疗效研究:一项前瞻性、开放性、多中心随机对照临床研究 

Public title:

Efficacy of Chloroquine and Lopinavir/ Ritonavir in mild/general novel coronavirus (CoVID-19) infections: a prospective, open-label, multicenter randomized controlled clinical study 

注册题目简写:

 

English Acronym:

 

研究课题的正式科学名称:

氯喹和洛匹那韦/利托那韦片治疗轻/普通型新型冠状病毒(CoVID-19)感染者的疗效研究:一项前瞻性、开放性、多中心随机对照临床研究 

Scientific title:

Efficacy of Chloroquine and Lopinavir/ Ritonavir in mild/general novel coronavirus (CoVID-19) infections: a prospective, open-label, multicenter randomized controlled clinical study 

研究课题代号(代码):

Study subject ID:

ZDWY.GRBK.011 

在二级注册机构或其它机构的注册号:

The registration number of the Partner Registry or other register:

 

申请注册联系人:

刘曦 

研究负责人:

夏瑾瑜 

Applicant:

Liu Xi 

Study leader:

Xia Jinyu 

申请注册联系人电话:

Applicant telephone:

+86 15992670630 

研究负责人电话:

Study leader's telephone:

+86 13823078064 

申请注册联系人传真 :

Applicant Fax:

 

研究负责人传真:

Study leader's fax:

 

申请注册联系人电子邮件:

Applicant E-mail:

liuxi26@mail.sysu.edu.cn 

研究负责人电子邮件:

Study leader's E-mail:

xiajinyu@mail.sysu.edu.cn 

申请单位网址(自愿提供):

Applicant website(voluntary supply):

http://www.zsufivehos.com/ 

研究负责人网址(自愿提供):

Study leader's website(voluntary supply):

http://www.zsufivehos.com/ 

申请注册联系人通讯地址:

广东省珠海市香洲区梅华东路52号 

研究负责人通讯地址:

广东省珠海市香洲区梅华东路52号 

Applicant address:

52 Meihua Road East, Xiangzhou District, Zhuhai, China 

Study leader's address:

52 Meihua Road East, Xiangzhou District, Zhuhai, China 

申请注册联系人邮政编码:

Applicant postcode:

519000 

研究负责人邮政编码:

Study leader's postcode:

519000 

申请人所在单位:

中山大学附属第五医院 

Applicant's institution:

The Fifth Affiliated Hospital Sun Yat-Sen University 

是否获伦理委员会批准:

是 

Approved by ethic committee:

Yes 

伦理委员会批件文号:

Approved No. of ethic committee:

中大五院【2020】伦字第(K15-1)号 

伦理委员会批件附件:

Approved file of Ethical Committee:

查看附件View

批准本研究的伦理委员会名称:

中山大学附属第五医院医学伦理委员会 

Name of the ethic committee:

Medical Ethics Committee of the Fifth Affiliated Hospital Sun Yat-Sen University 

伦理委员会批准日期:

Date of approved by ethic committee:

2020-02-09 

伦理委员会联系人:

黄瑾 

Contact Name of the ethic committee:

Huang Jin 

伦理委员会联系地址:

广东省珠海市香洲区梅华东路52号 

Contact Address of the ethic committee:

52 Meihua Road East, Xiangzhou District, Zhuhai, China 

伦理委员会联系人电话:

Contact phone of the ethic committee:

+86 0756-2528895 

伦理委员会联系人邮箱:

Contact email of the ethic committee:

 

研究实施负责(组长)单位:

中山大学附属第五医院 

Primary sponsor:

The Fifth Affiliated Hospital Sun Yat-Sen University 

研究实施负责(组长)单位地址:

广东省珠海市香洲区梅华东路52号 

Primary sponsor's address:

52 Meihua Road East, Xiangzhou District, Zhuhai, China 

试验主办单位(项目批准或申办者):

Secondary sponsor:

国家:

中国

省(直辖市):

广东

市(区县):

珠海

Country:

China

Province:

Guangdng

City:

Zhuhai

单位(医院):

中山大学附属第五医院

具体地址:

香洲区梅华东路52号

Institution
hospital:

The Fifth Affiliated Hospital Sun Yat-Sen University

Address:

52 Meihua Road East, Xiangzhou District

经费或物资来源:

中山大学 

Source(s) of funding:

Sun Yat-Sen University 

研究疾病:

2019新型冠状病毒感染 

Target disease:

2019 Novel Coronavirus Infection (CoVID-19) 

研究疾病代码:

 

Target disease code:

 

研究类型:

干预性研究 

Study type:

Interventional study 

研究所处阶段:

上市后药物 

Study phase:

研究目的:

比较氯喹和洛匹那韦/利托那韦片治疗轻/普通型CoVID-19感染者的疗效及安全性,建立规范化治疗方案。 

Objectives of Study:

Compare the efficacy and safety of chloroquine and lopinavir/ritonavir in patients with mild/general CoVID-19 infection, and establish a standardized treatment plan. 

药物成份或治疗方案详述:

氯喹是一种已知的4-氨基喹啉早在1944年起就应用于临床.氯喹可以改变内吞体的pH值, 对通过内吞体途径侵入细胞的病毒感染具有显著的抑制作用,如博尔纳病病毒、禽白血病病毒、塞卡病毒等。目前国际有研究团队发现氯喹在细胞水平上具有抗SARS- -CoV活性结合我们前期使用磷酸氯喹治疗2019-nCoV感染肺炎的患者5天内咽拭子核酸阴转率高达50%(5/10)显著优于使用洛匹那韦/利托那韦者。 而洛匹那韦/利托那韦为CYP3A抑制剂,经CYP3A代谢,国家卫健委发布的新型冠状病毒感染的肺炎诊疗方案(试行第五版)提出可试用洛匹那韦/利托那韦。然而我们前期使用发现使用洛匹那韦/利托那韦治疗的患者,收效甚微,5天内咽拭子核酸阴转率仅20%(3/15)。 基于以上证据,我们拟进一步扩大样本量在确诊2019-nCoV感染轻型/普通型患者中比较磷酸氯喹与洛匹那韦/利托那韦抗病毒治疗效果,评估药物的安全性,同时通过测定磷酸氯喹血药浓度,探索药物浓度与治疗效果及不良反应的相关性,以期提高患者治愈效率、加速病情好转、缩短住院时间及改善预后。 

Description for medicine or protocol of treatment in detail:

Chloroquine is a known 4-aminoquinoline that has been used clinically since 1944. Chloroquine can change the pH of endosomes and has a significant inhibitory effect on viral infections that invade cells through the endosome pathway, such as Borna disease virus, avian leukemia virus, Zika virus, etc. At present, an international research team found that chloroquine has anti-SARS-CoV activity at the cell level. In combination with our previous use of chloroquine phosphate to treat 2019-nCoV infected patients with pneumonia within 5 days, the negative conversion rate of throat swab nucleic acid was as high as 50% (5/10). Better than those using lopinavir/ritonavir. ??And lopinavir/ritonavir is a CYP3A inhibitor, which is metabolized by CYP3A. The new coronavirus-infected pneumonia diagnosis and treatment program (trial version 5) released by the National Health Commission proposes that lopinavir/ritonavir can be tried. However, our previous use found that patients treated with lopinavir/ritonavir had little effect, and the negative rate of nasopharyngeal swab nucleic acid was only 20% within 5 days (3/15). ??Based on the above evidence, we plan to further expand the sample size to compare the efficacy of chloroquine phosphate with lopinavir/ritonavir in the diagnosis of mild/general patients with 2019-nCoV infection, evaluate the safety of the drug, and measure the phosphate Chloroquine blood concentration, explore the correlation between drug concentration and treatment effect and adverse reactions, in order to improve the cure efficiency of patients, accelerate the improvement of the condition, shorten the length of hospital stay and improve the prognosis. 

研究设计:

随机平行对照 

Study design:

Parallel 

纳入标准:

(以下标准全部满足方可入选): (1) 年龄≥18岁; (2) 符合以下全部标准(参考诊疗方案第5版的确诊病例): ① 流行病学史; ② 临床表现(符合以下任意2条):发热;发病早期白细胞总数正常或降低,或淋巴细胞计数减少;胸部影像学早期呈现多发小斑片影及间质改变,以肺外带明显。进而发展为双肺多发磨玻璃影、浸润影,严重者可出现肺实变,胸腔积液少见。 ③ 确诊:疑似病例具备以下病原学证据之一者:呼吸道标本、血液标本或粪便标本实时荧光RT-PCR检测新型冠状病毒核酸阳性;上述标本病毒基因测序,与已知的新型冠状病毒高度同源。 ④ 轻型或普通型患者; ⑤ 用或者未用除磷酸氯喹、洛匹那韦/利托那韦以外的其他抗病毒药物。 

Inclusion criteria

(All the following criteria are met before being selected): 1. Aged >= 18 years; 2. Meet all the following criteria (refer to confirmed cases in the 5th edition of the diagnosis and treatment plan): (1) Epidemiological history; (2) Clinical manifestations (according to any of the following 2): fever; normal or decreased white blood cell count or reduced lymphocyte count in the early stages of onset; multiple small patchy shadows and interstitial changes in early chest imaging, which are evident in the extrapulmonary zone. Furthermore, it develops multiple ground glass infiltration and infiltrates in both lungs. In severe cases, pulmonary consolidation and pleural effusion are rare. (3) Confirmed: Suspected cases have one of the following pathogenic evidence: respiratory specimens, blood specimens, or fecal specimens are detected by real-time fluorescent RT-PCR to detect novel coronavirus nucleic acid; the above-mentioned specimens are genetically sequenced and highly homologous to known new coronaviruses . (4) Light or ordinary patients; (5) With or without anti-viral drugs other than chloroquine phosphate, lopinavir/ritonavir. 

排除标准:

(如果受试者符合以下条件的任何一条,则不能进入本研究): 1. 明确对磷酸氯喹类、洛匹那韦、利托那韦药物过敏史的患者; 2. 患有血液系统疾病的患者; 3. 患有慢性肝、肾疾病并达到终末期的患者; 4. 患有心律失常、慢性心脏病的患者; 5. 已知患有视网膜疾病、听力减退或听力丧失的患者; 6. 已知患有精神类疾病的患者; 7. 因原有基础疾病必须使用洋地黄类药物的患者; 8. 胰腺炎; 9. 血友病; 10. 蚕豆病; 11. 处于妊娠期的女性患者。 

Exclusion criteria:

(Subjects cannot enter the study if they meet any of the following conditions): 1. Patients with a history of allergy to chloroquine phosphate, lopinavir, and ritonavir; 2. Patients with hematological diseases; 3. Patients with chronic liver and kidney disease and reaching the end stage; 4. Patients with arrhythmia and chronic heart disease; 5. Patients known to have retinal disease, hearing loss or hearing loss; 6. Patients with known mental illness; 7. Patients who must use digitalis because of the original underlying disease; 8. Pancreatitis; 9. Hemophilia; 10. Broad bean disease; 11. Female patients during pregnancy. 

研究实施时间:

Study execute time:

From2020-02-12To 2020-12-31 

干预措施:

Interventions:

组别:

试验组

样本量:

56

Group:

experimental group

Sample size:

干预措施:

磷酸氯喹

干预措施代码:

Intervention:

Chloroquine Phosphate

Intervention code:

组别:

对照组

样本量:

56

Group:

control group

Sample size:

干预措施:

洛匹那韦/利托那韦

干预措施代码:

Intervention:

Lopinavir / Ritonavir

Intervention code:

研究实施地点:

Countries of recruitment and research settings:

国家:

中国 

省(直辖市):

广东 

市(区县):

珠海 

Country:

China 

Province:

Guangdong 

City:

Zhuhai 

单位(医院):

中山大学附属第五医院 

单位级别:

三级甲等 

Institution
hospital:

The Fifth Affiliated Hospital Sun Yat-Sen University  

Level of the institution:

Tertiary A 

测量指标:

Outcomes:

指标中文名:

总体住院时间

指标类型:

主要指标 

Outcome:

Length of stay

Type:

Primary indicator 

测量时间点:

测量方法:

Measure time point of outcome:

Measure method:

指标中文名:

转为重型时间

指标类型:

主要指标 

Outcome:

Length of severe

Type:

Primary indicator 

测量时间点:

测量方法:

Measure time point of outcome:

Measure method:

指标中文名:

治疗期间氧合指数

指标类型:

主要指标 

Outcome:

oxygenation index during treatment

Type:

Primary indicator 

测量时间点:

第 1、3、5、7、10、14、21、28天

测量方法:

Measure time point of outcome:

Day 1, 3, 5, 7, 10, 14, 21, 28

Measure method:

指标中文名:

28天全因死亡率

指标类型:

主要指标 

Outcome:

all-cause mortality in 28 days

Type:

Primary indicator 

测量时间点:

测量方法:

Measure time point of outcome:

Measure method:

指标中文名:

外周血细胞计数(包括白细胞、淋巴细胞、中性粒细胞等)

指标类型:

主要指标 

Outcome:

Peripheral blood cell count (including white blood cells, lymphocytes, neutrophils, etc.)

Type:

Primary indicator 

测量时间点:

第 1、3、5、7、10、14、21、28天

测量方法:

Measure time point of outcome:

Day 1, 3, 5, 7, 10, 14, 21, 28

Measure method:

指标中文名:

降钙素原

指标类型:

主要指标 

Outcome:

procalcitonin

Type:

Primary indicator 

测量时间点:

第 1、3、5、7、10、14、21、28天

测量方法:

Measure time point of outcome:

Day 1, 3, 5, 7, 10, 14, 21, 28

Measure method:

指标中文名:

C反应蛋白

指标类型:

主要指标 

Outcome:

C-reactive protein

Type:

Primary indicator 

测量时间点:

第 1、3、5、7、10、14、21、28天

测量方法:

Measure time point of outcome:

Day 1, 3, 5, 7, 10, 14, 21, 28

Measure method:

指标中文名:

炎症因子(包括IL-6、IL-10、TNF-α等)

指标类型:

主要指标 

Outcome:

Inflammatory factors (including IL-6, IL-10, TNF-α, etc.)

Type:

Primary indicator 

测量时间点:

第 1、3、5、7、10、14、21、28天

测量方法:

Measure time point of outcome:

Day 1, 3, 5, 7, 10, 14, 21, 28

Measure method:

指标中文名:

淋巴细胞亚群及补体

指标类型:

主要指标 

Outcome:

Lymphocyte subsets and complement

Type:

Primary indicator 

测量时间点:

第 1、3、5、7、10、14、21、28天

测量方法:

Measure time point of outcome:

Day 1, 3, 5, 7, 10, 14, 21, 28

Measure method:

指标中文名:

凝血指标(凝血酶原时间、活化部分凝血酶原时间、纤维蛋白原、D-二聚体、血小板计数)

指标类型:

主要指标 

Outcome:

Coagulation indicators (prothrombin time, activated partial prothrombin time, fibrinogen, D-dimer, platelet count)

Type:

Primary indicator 

测量时间点:

第 1、3、5、7、10、14、21、28天

测量方法:

Measure time point of outcome:

Day 1, 3, 5, 7, 10, 14, 21, 28

Measure method:

指标中文名:

病毒核酸

指标类型:

主要指标 

Outcome:

Virus nucleic acid

Type:

Primary indicator 

测量时间点:

第1、2、3、4、5、6、7、8、9、10、14、21、28天

测量方法:

Measure time point of outcome:

Day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 21, 28

Measure method:

指标中文名:

其他(肝肾功能、肌酶、肌红蛋白)

指标类型:

次要指标 

Outcome:

Others (liver and kidney function, muscle enzymes, myoglobin)

Type:

Secondary indicator 

测量时间点:

第1、3、5、7、10、14、21、28天

测量方法:

Measure time point of outcome:

Day 1, 3, 5, 7, 10, 14, 21, 28

Measure method:

指标中文名:

治疗期间不良反应事件(包括严重胃肠道反应、白细胞减少、新发视网膜病、大面积皮肤损害等)

指标类型:

副作用指标 

Outcome:

Adverse events during treatment (including severe gastrointestinal reactions, leukopenia, new retinopathy, large-scale skin damage, etc.)

Type:

Adverse events 

测量时间点:

测量方法:

Measure time point of outcome:

Measure method:

指标中文名:

氯喹血药浓度

指标类型:

附加指标 

Outcome:

Chloroquine blood concentration

Type:

Additional indicator 

测量时间点:

第1、3、5、7、10、14、21、28天

测量方法:

Measure time point of outcome:

Day 1, 3, 5, 7, 10, 14, 21, 28

Measure method:

采集人体标本:

Collecting sample(s)
from participants:

标本中文名:

呼吸道、血液、粪便或其他所有样本

组织:

Sample Name:

Respiratory tract, blood, feces or all other samples

Tissue:

人体标本去向

使用后销毁 

说明

Fate of sample:

Destruction after use 

Note:

征募研究对象情况:

Recruiting status:

正在进行

Recruiting

年龄范围:

Participant age:

最小 Min age years
最大 Max age years

性别:

男女均可

Gender:

Both

随机方法(请说明由何人用什么方法产生随机序列):

试验开始前,由统计专家根据统计软件对1~112数字进行随机分配,产生随机分配表,所选择的区组长度和随机种子数等参数一同保存于统计专家处。统计专家事先根据随机分配表,按入选顺序从小到大给予随机编号(1-112),每个随机编号对应一个信封,信封内装着对应的随机号,将信封封好后交给负责筛选入组的研究人员。筛选合格的受试者,按照入组的先后顺序领到信封,拆开信封后取出随机号码交给负责治疗及观察的研究人员,由该研究人员联系统计专家,统计专家根据随机分配表告知该随机号对应的组别,从而将受试者随机分配到试验组或对照组,并进行相应的治疗和访视观察。每位受试者的随机号是唯一的,在整个试验过程中保持不变。

Randomization Procedure (please state who generates the random number sequence and by what method):

Prior to the start of the experiment, a statistical expert randomly assigns 1 to 112 numbers according to the statistical software to generate a random allocation table. The selected block length and random seed number are stored together with the statistical expert.

盲法:

开放

Blinding:

Open label

原始数据公开时间:

The time of sharing IPD:

试验完成后6个月内公开/Within six months after the trial complete

共享原始数据的方式(说明:请填入公开原始数据日期和方式,如采用网络平台,需填该网络平台名称和网址):

发表论文 2021.12

The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url):

publish 2021.12

数据采集和管理(说明:数据采集和管理由两部分组成,一为病例记录表(Case Record Form, CRF),二为电子采集和管理系统(Electronic Data Capture, EDC),如ResMan即为一种基于互联网的EDC:

病例记录表

Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture:

Case Record Form, CRF

数据管理委员会:

Data Managemen Committee:

无/No

注册人:

Name of Registration:

 2020-02-11
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