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间充质干细胞在ABO血型不符肝移植中的作用及其治疗策略
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注册号:

Registration number:

ChiCTR2000037732 

最近更新日期:

Date of Last Refreshed on:

2020-11-01 

注册时间:

Date of Registration:

2020-08-31 

注册号状态:

补注册  

Registration Status:

Retrospective registration  

注册题目:

间充质干细胞在ABO血型不符肝移植中的作用及其治疗策略 

Public title:

Therapeutic Strategy and the Role of Mesenchymal Stromal Cells for ABO Incompatible Liver Transplantation 

注册题目简写:

 

English Acronym:

 

研究课题的正式科学名称:

人脐带间充质干细胞应用于严重肝衰竭并接受ABO血型不符肝移植患者中的临床研究 

Scientific title:

Allogeneic umbilical cord-derived mesenchymal stem cells (UC-MSCs) for patients with severe liver failure and receiving ABO incompatible liver transplantation 

研究课题代号(代码):

Study subject ID:

 

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:

张英才 

研究负责人:

杨扬 

Applicant:

Yingcai Zhang 

Study leader:

Yang Yang 

申请注册联系人电话:

Applicant telephone:

+86 15902096055 

研究负责人电话:

Study leader's telephone:

+86 18922102666 

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:

zhangyc3@mail.sysu.edu.cn 

研究负责人电子邮件:

Study leader's E-mail:

yysysu@163.com 

申请单位网址(自愿提供):

Applicant website(voluntary supply):

 

研究负责人网址(自愿提供):

Study leader's website(voluntary supply):

 

申请注册联系人通讯地址:

广东省广州市天河区天河路600号 

研究负责人通讯地址:

广东省广州市天河区天河路600号 

Applicant address:

600 Tianhe Road, Tianhe District, Guangzhou, China 

Study leader's address:

600 Tianhe Road, Tianhe District, Guangzhou, China 

申请注册联系人邮政编码:

Applicant postcode:

 

研究负责人邮政编码:

Study leader's postcode:

 

申请人所在单位:

中山大学附属第三医院 

Applicant's institution:

The Third Affiliated Hospital of 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:

2020-07 

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:

中山大学附属第三医院伦理委员会 

Name of the ethic committee:

Ethics committee of The Third Affiliated Hospital of Sun Yat-sen University 

伦理委员会批准日期:

Date of approved by ethic committee:

2020-07-16 

伦理委员会联系人:

刘畅 

Contact Name of the ethic committee:

Chang Liu 

伦理委员会联系地址:

广东省广州市天河区天河路600号 

Contact Address of the ethic committee:

600 Tianhe Road, Tianhe District, Guangzhou, China 

伦理委员会联系人电话:

Contact phone of the ethic committee:

 

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:

中山大学附属第三医院 

Primary sponsor:

The Third Affiliated Hospital of Sun Yat-Sen University 

研究实施负责(组长)单位地址:

广东省广州市天河区天河路600号 

Primary sponsor's address:

600 Tianhe Road, Tianhe District, Guangzhou, 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):

广州

Country:

China

Province:

Guangdong

City:

Guangzhou

单位(医院):

中山大学附属第三医院

具体地址:

天河区天河路600号

Institution
hospital:

The Third Affiliated Hospital of Sun Yat-Sen University

Address:

600 Tianhe Road, Tianhe District

经费或物资来源:

广州市科技计划项目 

Source(s) of funding:

Science and Technology Planning Project of Guangzhou city 

研究疾病:

肝衰竭 

Target disease:

severe hepatic failure 

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:

I期+II期 

Study phase:

1-2 

研究目的:

利用间充质干细胞的免疫调节和促进组织修复再生等生物学特点,使用间充质干细胞替代ABO血型不符肝移植免疫抑制方案中利妥昔单抗(美罗华)的应用,从而降低ABO血型不符肝移植术后并发症(尤其是术后严重感染、胆道并发症)发生率,提高受体、移植物的存活率。制定间充质干细胞应用于ABO血型不符肝移植术后并发症防治的新型免疫抑制方案,并在国内外推广。 

Objectives of Study:

The aim of this study is to evaluate the safety and efficacy of multi-doses allogeneic UC-MSCs for 6 months versus rituximab treatment in severe hepatic failure patients who received ABO-i LT and prone to develop antibody-mediated rejection (AMR). To complete 12 months of randomized, parallel comparisons of UC-MSCs therapy versus rituximab treatment, the primary outcomes, including the assessments of MSC-related adverse events (fever, headache, rash, vomiting, diarrhea and carcinogenesis) and the incidence of allograft rejection (AR) [including antibody-mediated rejection (AMR) and acute cellular rejection (ACR)], and the secondary outcomes (containing: 1. the evaluation of graft and recipient survivals at month 12; 2. the causes of death; 3. the changes of graft function; 4. the incidence of postoperative complications [including biliary complications and specific infections]; 5. the changes of intrahepatic immune cell populations) were investigated. 

药物成份或治疗方案详述:

试验组:间充质干细胞(MSC)组免疫抑制方案 huc-MSCs+甲强龙、他克莫司、霉酚酸酯、巴利昔单抗四联免疫抑制+丙种球蛋白(IVIG) 1.MSC应用方案: MSC每次用量:1×10^6MSCs/kg体重 MSC用法:供肝恢复灌流后10%MSCs通过门静脉注入,90%MSCs通过外周静脉滴入;术后1W、2W、4W、8W、12W、16W、20W、24W分别从外周静脉滴入MSCs一次。 2.四联免疫抑制方案: 甲强龙:术中1g静滴,术后第一天500mg静滴,术后第二天60mg Q6h静滴,随后每日递减40mg,直至20mg Q12h,随后改为口服48mg Qd,每三天减量8mg,直至口服8mg/天,至少维持1年。 他克莫司:术后第三天加用,2mg/天,调整血药浓度10-15 ng/mL。 霉酚酸酯:术后第三天加用,1.5g/天,视肝功、肾功、FK浓度等调整。 巴利昔单抗:术中及术后第4天各用20mg静滴。 3.丙种球蛋白(IVIG)应用方案: 术后1-7天IVIG 10g/天静脉滴入。 对照组:美罗华组免疫抑制方案 美罗华+甲强龙、他克莫司、霉酚酸酯、巴利昔单抗四联免疫抑制+丙种球蛋白(IVIG) 1.美罗华应用方案: 术后立即予单剂美罗华静脉滴注(美罗华用量按375mg/m^2计算),滴入速度为第1小时50mg,随后改为每小时100mg。滴注前予地塞米松5mg静注预防过敏。 2.免疫吸附+甲强龙、他克莫司、霉酚酸酯、巴利昔单抗四联免疫抑制+丙种球蛋白(IVIG)应用方案同 MSC组。 

Description for medicine or protocol of treatment in detail:

1. The control group: Standard immunosuppressive strategy and rituximab(375mg/m^2) 2. The case group: Standard immunosuppressive strategy and 9 doses of UC-MSCs infusion(1.0×10^6/kg) 

研究设计:

随机平行对照 

Study design:

Parallel 

纳入标准:

1.年龄在18至65岁之间的男性或女性。 2.MELD评分> 25。 3.根据研究中心标准,符合ABO不符肝移植条件的严重肝功能衰竭患者。 4.进行ABO不符肝移植的严重肝衰竭患者。 5.能够理解研究的目的和风险。 6.在进行任何评估之前,患者或代理人必须给予书面知情同意。 

Inclusion criteria

1. Male or female, 18 to 65 years of age; 2. Meld score >25; 3. Eligibility for ABO-incompatibility liver transplantation for severe liver failure according to center standard; 4. Undergoing ABO incompatibility liver transplantation for severe liver failure; 5. Capable of understanding the purpose and risk of the study; 6. Patients or proxy must give written informed consent before any assessment is performed. 

排除标准:

1.多器官移植。 2.过去曾行器官移植手术。 3.术前ABO血型抗体(IgM和IgG)滴度> 1:64。 4.孕妇或哺乳期妇女。 5.恶性肿瘤病史。 6.肺栓塞史。 7.自身免疫病患者。 8. HIV血清阳性或HTLV血清阳性。 9.血栓形成患者。 10.术前门静脉存在血栓。 11.滥用毒品或酒精。 12.UC-MSCs输注的特定禁忌症。 13.移植术前存在严重感染(包括细菌,真菌,病毒和寄生虫)。 14.任何可能影响研究参与和/或研究结果的临床相关疾病。 15.已经参与其他临床试验。 16.研究者认为不愿意或无法遵循研究方案的患者。 

Exclusion criteria:

1. Undergoing multi-organ transplantations; 2. Receiving any form of solid organ transplantation in the past; 3. ABO blood group antibodies (IgM and IgG) before surgery >1:64; 4. Pregnant or breastfeeding women; 5. Hepato-biliary malignancies or history of any extrahepatic malignancy; 6. History of pulmonary embolism; 7. Patients with active autoimmune disease; 8. HIV seropositive or HTLV seropositive; 9. Patients with thrombophilia; 10. Pre-existent thrombosis of portal vein; 11. Known abuse for drugs or alcohol; 12. Specific contraindication to UC-MSCs infusion; 13. Severe infection before transplantation (including bacterial, fungus, virus and parasite); 14. Any clinical-relevant condition that might affect study participation and/or study results; 15. Participation in any other intervention trial; 16. Unwillingness or inability to following the study protocol in the investigators opinion. 

研究实施时间:

Study execute time:

From2016-08-01To 2018-08-31 

征募观察对象时间:

Recruiting time:

From2016-08-01To 2020-07-26 

干预措施:

Interventions:

组别:

试验组

样本量:

11

Group:

Experimental group

Sample size:

干预措施:

人脐带间充质干细胞

干预措施代码:

Intervention:

Umbilical cord-derived mesenchymal stem cells (UC-MSCs)

Intervention code:

组别:

对照组

样本量:

11

Group:

Control group

Sample size:

干预措施:

美罗华(利妥昔单抗)

干预措施代码:

Intervention:

Rituximab

Intervention code:

研究实施地点:

Countries of recruitment and research settings:

国家:

中国 

省(直辖市):

广东省 

市(区县):

广州市 

Country:

China 

Province:

Guangdong 

City:

Guangzhou 

单位(医院):

中山大学附属第三医院 

单位级别:

三级甲等医院 

Institution
hospital:

The Third Affiliated Hospital of Sun Yat-Sen University  

Level of the institution:

Tertiary A Hospital 

测量指标:

Outcomes:

指标中文名:

急性排斥反应

指标类型:

主要指标 

Outcome:

Acute rejection

Type:

Primary indicator 

测量时间点:

测量方法:

Measure time point of outcome:

Measure method:

指标中文名:

人脐带间充质干细胞的安全性评估

指标类型:

副作用指标 

Outcome:

The safety of multi-doses UC-MSCs administration

Type:

Adverse events 

测量时间点:

测量方法:

Measure time point of outcome:

Measure method:

指标中文名:

移植患者与移植物的1年存活率

指标类型:

次要指标 

Outcome:

Graft and recipient survivals at transplantation of 12 months

Type:

Secondary indicator 

测量时间点:

测量方法:

Measure time point of outcome:

Measure method:

指标中文名:

肝功能指标

指标类型:

次要指标 

Outcome:

The changes of graft function

Type:

Secondary indicator 

测量时间点:

测量方法:

Measure time point of outcome:

Measure method:

指标中文名:

肝移植术后严重感染发生率

指标类型:

次要指标 

Outcome:

The incidence of postoperative complications: Severe infection

Type:

Secondary indicator 

测量时间点:

测量方法:

Measure time point of outcome:

Measure method:

指标中文名:

肝移植术后胆道并发症发生率

指标类型:

次要指标 

Outcome:

The incidence of postoperative complications: Biliary complications

Type:

Secondary indicator 

测量时间点:

测量方法:

Measure time point of outcome:

Measure method:

采集人体标本:

Collecting sample(s)
from participants:

标本中文名:

血液

组织:

静脉血

Sample Name:

Blood

Tissue:

Vein

人体标本去向

使用后销毁 

说明

Fate of sample:

Destruction after use 

Note:

标本中文名:

肝脏穿刺组织

组织:

肝脏

Sample Name:

Liver biopsy tissue

Tissue:

Liver

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:

结束

Completed

年龄范围:

Participant age:

最小 Min age 18 years
最大 Max age 65 years

性别:

男性

Gender:

Male

随机方法(请说明由何人用什么方法产生随机序列):

本项目临床试验研究遵循开放性、随机、对照的原则,入组22例ABO血型不符合肝移植患者进行临床试验。由不参与本试验的统计学家将患者随机平均分为间充质干细胞组和美罗华组,并遵循以下原则: 1. 运用excel中的函数rand,每个研究对象生成一个随机数; 2. 根据随机数的大小排序,依次给每个研究对象编号; 3. 编号为奇数的研究对象为试验组,偶数的为对照组。

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

Patients were randomly assigned to a standard immunosuppressive strategy and rituximab group(375mg/m^2)(The control group) or a standard immunosuppressive strategy and 9 doses of UC-MSCs infusion group(1.0×10^6/kg)(The case group) in a 1:1 ratio by computer-generated random sequence. The assignment information is stored in an

盲法:

开放性临床研究

Blinding:

This is an open-label study; both participants and the research teams were unblinded to treatment allocation.

是否共享原始数据:

IPD sharing

是Yes

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):

方式:Excel 电子数据表格;时间:2021.1.26

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

The IPD will be Shared in an Excel spreadsheet on January 26, 2021

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

数据与安全监察委员会:

Data and Safety Monitoring Committee:

有/Yes

注册人:

Name of Registration:

 2020-08-31
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