中国临床试验注册中心 - 世界卫生组织国际临床试验注册平台一级注册机构

注册号： Registration number：	ChiCTR2000040220
最近更新日期： Date of Last Refreshed on：	2021-01-25 17:03:50
注册时间： Date of Registration：	2020-11-25 00:00:00
注册号状态：	预注册
Registration Status：	Prospective registration
注册题目：	一项随机、对照临床研究：评估脐带间充质干细胞治疗中重度克罗恩病的临床有效性和安全性
Public title：	A randomized, controlled trial to evaluate the clinical efficacy and safety of umbilical cord mesenchymal stem cells in the treatment of moderate to severe Crohn's disease
注册题目简写：
English Acronym：
研究课题的正式科学名称：	一项随机、对照临床研究：评估脐带间充质干细胞治疗中重度克罗恩病的临床有效性和安全性
Scientific title：	A randomized, controlled trial to evaluate the clinical efficacy and safety of umbilical cord mesenchymal stem cells in the treatment of moderate to severe Crohn's disease
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：	李珊	研究负责人：	钟岚、刘中民
Applicant：	Shan Li	Study leader：	Lan Zhong & Zhongmin Liu
申请注册联系人电话： Applicant telephone：	+86 18355435170	研究负责人电话： Study leader's telephone：	+86 13162099450
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：	18355435170@163.com	研究负责人电子邮件： Study leader's E-mail：	lanzhong@tongji.edu.cn
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：	上海市浦东新区云台路1800号	研究负责人通讯地址：	上海市浦东新区云台路1800号
Applicant address：	1800 Yuntai Road, Pudong New Area, Shanghai, China	Study leader's address：	1800 Yuntai Road, Pudong New Area, Shanghai, China
申请注册联系人邮政编码： Applicant postcode：	200123	研究负责人邮政编码： Study leader's postcode：	200123
申请人所在单位：	上海市东方医院
Applicant's institution：	Shanghai East Hospital
研究负责人所在单位：	上海市东方医院
Affiliation of the Leader：	Shanghai East Hospital

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】研审第（081）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：	上海市东方医院医学伦理委员会
Name of the ethic committee：	Medical Ethics Committee of Shanghai East Hospital
伦理委员会批准日期： Date of approved by ethic committee：	2020-10-30 00:00:00
伦理委员会联系人：	孙翰东
Contact Name of the ethic committee：	Handong Sun
伦理委员会联系地址：	上海市浦东新区云台路1800号
Contact Address of the ethic committee：	1800 Yuntai Road, Pudong New Area, Shanghai, 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：

上海市东方医院

Primary sponsor：

Shanghai East Hospital

研究实施负责（组长）单位地址：

上海市浦东新区云台路1800号

Primary sponsor's address：

1800 Yuntai Road, Pudong New Area, Shanghai, 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)：	上海市	市(区县)：
Country：	China	Province：	Shanghai	City：
单位(医院)：	上海市东方医院	具体地址：	上海市浦东新区云台路1800号
Institution hospital：	Shanghai East Hospital	Address：	1800 Yuntai Road, Pudong New Area, Shanghai, China

经费或物资来源：

申办方提供资金

Source(s) of funding：

Funds provided by the applicant

研究疾病：

克罗恩病

Target disease：

Crohn's disease

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：

治疗新技术临床试验

Study phase：

New Treatment Measure Clinical Study

研究设计：

随机平行对照

Study design：

Parallel

研究目的：

评价经静脉+经肠镜病变组织局部黏膜下注射脐带间充质干细胞治疗在中重度克罗恩病中诱导临床缓解的有效性和安全性，为CD患者提供一种新型微创干细胞治疗方案，减少克罗恩病患者对于免疫抑制剂或生物制剂及手术的需求，减少并发症和药物相关不良反应的发生，改善患者的生存质量。

Objectives of Study：

Evaluation by vein and the colonoscopy diseased tissue between local submucosal injection of umbilical cord mesenchymal stem cell therapy in the relation between Crohn's disease induced efficacy and safety of clinical response, to provide patients with CD a new minimally invasive treatment of stem cells, reduce Crohn disease for immune inhibitors or biological preparation and operation requirements, reduce the occurrence of complications and drug-related adverse reaction, improve the quality of life of patients.

药物成份或治疗方案详述：

间充质干细胞的制备：基于上海交通大学-上海智能诊疗仪器工程技术研究中心细胞实验室的IMUACT (Immuno-Modulatory Umbilical cord tissue-derived Allogeneic Cell Therapy)技术平台，提取并纯化多根脐带组织来源的间充质干细胞，使用无血清培养技术结合智能化细胞工厂培养系统进行大量扩增培养。培养至5代的细胞，在临床应用前，经纳米技术及应用国家工程研究中心质量鉴定达到以下要求：①无肉眼结块；②形态特征：间充质干细胞呈梭形；③细胞存活率≥95%；④无致病微生物（细菌、真菌、支原体、梅毒、乙肝病毒、丙肝病毒、巨细胞病毒和疱疹病毒）；⑤内毒素≤0.5EU/mL；⑥表征纯度和均一性，具有CD73、CD90和CD105阳性（≥95％），CD45、CD34和HLA-DR阴性（≤2％）的特征和纯度模式；⑦细胞在免疫缺陷小鼠上不成瘤；⑧有分化成骨、成脂、成软骨的生物学效应。

Description for medicine or protocol of treatment in detail：

The preparation of mesenchymal stem cells: based on the Shanghai Jiaotong University - Shanghai intelligent diagnosis instrument engineering technology research center (Cell lab IMUACT (Immuno - Modulatory Umbilical cord tissue-derived Allogeneic Cell Therapy) technology platform, extraction, and purification multiple roots between the source of mesenchymal stem cells, Umbilical cord organization using serum-free culture technology combined with intelligent Cell factory system to cultivate a large number of augmentation. The cells cultured to 5 generations before clinical application were identified by the National Engineering Research Center for nanotechnology and application to meet the following requirements: No gross caking; Morphological characteristics: Mesenchymal stem cells were fusiform; Cell survival rate >= 95%; No pathogenic microorganisms (bacteria, fungi, mycoplasma, syphilis, hepatitis B virus, Hepatitis C virus, cytomegalovirus and herpes virus); Endotoxin <= 0.5EU/mL; Characterization of purity and uniformity, with CD73, CD90, and CD105 positive (>= 95%), CD45, CD34, and HLA-DR negative (<= 2%) characteristics and purity pattern; A cells were not tumors in immunodeficient mice. There are biological effects of differentiation into bone, fat, and cartilage.

纳入标准：

Inclusion criteria

1) At the time of randomization, subjects aged between 18 and 75 years;
2) Subjects with at least 3 months of diagnosis of ileal, colonic, or ileal Crohn's disease were recorded when randomized;
3) Having Crohn's disease at present and having a Crohn's disease activity index (CDAI) score >=220 and <=450;
4) Screening for active diseases endoscopic confirmatory examination confirmed the presence of active inflammation and ulcer in the subjects;
5) Subjects must be free from active, latent, or undertreated MYCO bacterium tuberculosis infection;
6) All fertile women and all men must be willing to use at least one effective method of contraception from the time they sign the informed consent form and throughout the study period until 1 month after the last administration of the study drug;
7) Subjects who are willing and able to visit and undergo treatment plans, laboratory tests, and other study procedures from the program;
8) Ability to sign an informed consent (dated) indicating that the subject has been informed of all relevant parts of the study;
9) Subjects receiving nonprohibited combination therapy for any reason must maintain a stable treatment regimen defined as no stem cell treatment or no change in dose 7 days prior to the initial injection of stem cells or 5 half-lives (whichever is longer).

排除标准：

1）临床表现为未定型结肠炎或提示溃疡性结肠炎受试者。
2）进行造口、胃或回肠肛门储袋术、直肠结肠切除术或全结肠切除术以及患有症状性狭窄、肠穿孔史、疑似脓肿，及活动性引流瘘管的CD受试者。
3）过去6个月内接受过肠切除术或在研究期间可能需要进行手术的受试者。
4）有证据显示致病性肠道感染的受试者。内镜筛查30天内患有艰难梭菌或其他肠道感染的受试者，或艰难梭菌毒素测定或其他病原体筛查阳性的受试者。
5）筛选访视时存在造血功能障碍证据的受试者：
- 血红蛋白水平<9.0 g/dL或红细胞压积<30%。
- 白细胞绝对计数<3.0×109（<3000/mm3）或中性粒细胞绝对计数（ANC）<1.2×109/L（<1200/mm3）。
-存在血小板减少症，定义为血小板计数<100×109/L（<100,000/mm3）。
6）筛选访视时总胆红素、天冬氨酸氨基转移酶（AST）或丙氨酸氨基转移酶（ALT）超过正常上限2倍的受试者。将排除肝硬化患者。
7） eGFR≤60 mL/min（根据Cockcroft-Gault计算）的受试者或接受血液透析的患者。
8）目前患有或基线前1个月内存在临床重大感染，或既往发生过一次以上带状疱疹、播散性带状疱疹史（发生一次）以及其他研究者认为可能会因参与研究而出现加重的感染史，或筛选2周内需要抗菌治疗的任何感染的受试者。
9）目前可能接受任何活病毒疫苗接种或基线前8周内接受过任何活病毒疫苗接种的受试者。
10）一级亲属患有遗传性免疫缺陷的受试者。
11）存在任何淋巴组织增生性疾病史（例如：EBV相关淋巴组织增生性疾病）、淋巴瘤、白血病、骨髓增生性疾病、多发性骨髓瘤，或提示存在现症淋巴系统疾病的体征和症状等病史。
12）既往接受过任何淋巴细胞耗竭剂/疗法治疗的受试者。既往接受过利妥昔单抗或其他选择性B淋巴细胞耗竭剂治疗，但在基线前至少1年内未接受此类治疗的受试者，则符合研究资格。
13）孕妇或哺乳期妇女或计划入组研究期间妊娠的女性受试者。
14）既往存在酒精或药物滥用史且基线前戒断时间不足6个月。
15）筛选期12导联心电图证实存在如果入组本研究将可能影响其安全性或影响研究结果判读的临床相关异常的受试者。
16）基线前2个月内献血超过500 mL的受试者。
17）筛选访视4周内经历重大创伤或进行大手术的受试者。
18）筛选期或基线期体温≥38℃的受试者。
19）患有恶性肿瘤或有恶性肿瘤病史的受试者。
20）感染人类免疫缺陷病毒（HIV）或乙型肝炎病毒或丙型肝炎病毒的受试者。
21）研究者认为不合作或不能依从研究流程的受试者。
22）其他任何研究者认为会导致受试者不适于入选研究的情况。
23）既往存在或目前存在着有临床意义的心血管、神经、精神、肾、肝、免疫、消化道、泌尿生殖系统、神经系统、肌肉骨骼、皮肤、感觉、内分泌（包括未控制的糖尿病或甲状腺疾病）或未控制血液学异常证据的受试者。“有意义”定义为研究者认为参与研究会对受试者的安全性造成风险或研究期间疾病/病症加重时会影响有效性或安全性分析。

Exclusion criteria：

1) The clinical manifestations are unshaped colitis or ulcerative colitis;
2) CD subjects who underwent an ostomy, gastric or ileum anal pouch, proctocolectomy, or total colectomy, as well as symptomatic stenosis, history of intestinal perforation, suspected abscess, and active drainage fistula;
3) Subjects who have undergone enterectomy in the past 6 months or may require surgery during the study period;
4) Subjects with evidence of pathogenic intestinal infection. Subjects screened for Clostridium difficile or other intestinal infections within 30 days of endoscopy, or subjects screened positive for Clostridium difficile toxin or other pathogens;
5) Screen the subjects with evidence of hematopoietic dysfunction during the visit:
- Hemoglobin level<9.0g /dL or hematocrit <30%.
- Absolute leukocyte count <3.0 x 10^9 (<3000 cells/mm3), absolute count of neutrophils (ANC) <1.2 x 10^9/L (<1200 cells/mm3);
- Presence of thrombocytopenia, defined as platelet count <100 x 10^9/L (<100000 cells/mm3);
6) Screening subjects whose total bilirubin, aspartate aminotransferase (AST), or alanine aminotransferase (ALT) exceeded 2 times of the normal upper limit at the time of interview. Exclude patients with cirrhosis;
7) Subjects with eGFR<=60 mL/min (calculated according to Cockcroft-Gault) or patients receiving hemodialysis;
8) currently suffering from, or within a month before the baseline clinical significant infection, or always happened more than once herpes zoster, history of disseminated herpes zoster and other researchers think that may be aggravated by the study of the history of infection, or screening antibacterial treatment 2 weeks need any infected subjects;
9) Subjects who may currently receive any live virus vaccine or who have received any live virus vaccine in the 8 weeks prior to baseline;
10) Subjects whose first-degree relatives have inherited immune deficiency;
11) A history of any lymphoproliferative disease (e.g., EBV-associated lymphoproliferative disease), lymphoma, leukemia, myeloproliferative disease, multiple myeloma, or signs and symptoms suggestive of the present lymphoproliferative disease;
12) Subjects who have previously received any lymphocyte depletion agent/therapy. Subjects who had previously received rituximab or other selective B lymphocyte depletion agents but had not received such treatment for at least 1 year prior to baseline were eligible for the study;
13) Pregnant or lactating women or female subjects planning to be enrolled in the study during pregnancy;
14) A history of alcohol or drug abuse and withdrawal less than 6 months prior to baseline;
15) During the screening, ECG findings confirmed the presence of clinically relevant abnormalities that would affect the safety or interpretation of study results if included in the study;
16) Subjects who donated more than 500 mL within 2 months before baseline;
17) Screening of subjects who have undergone major trauma or major surgery within 4 weeks;
18) Screen subjects with body temperature >=38 degree C at the stage or baseline;
19) Subjects with or with a history of the malignant tumor;
20) Subjects infected with human immunodeficiency virus (HIV) or hepatitis B virus or hepatitis C virus;
21) Subjects considered by the investigator to be uncooperative or unable to comply with study procedures;
22) Any other conditions that the investigator considers would render the subject unfit for inclusion in the study;
23) Prior or present presence of clinically significant cardiovascular, neurological, psychiatric, renal, liver, immune, digestive, urogenital, nervous, musculoskeletal, skin, sensory, endocrine (including uncontrolled diabetes or thyroid disease) or evidence of uncontrolled hematologic abnormalities. "Meaningful" is defined as the investigator's belief that participation in the study would pose a risk to the subject's safety or that the aggravation of disease/illness during the study would affect the effectiveness or safety analysis.

研究实施时间：

Study execute time：

从 From 2020-11-13 00:00:00至 To 2023-09-30 00:00:00

征募观察对象时间：

Recruiting time：

从 From 2020-11-13 00:00:00 至 To 2023-06-30 00:00:00

干预措施：

Interventions：

组别：	MSC联合治疗组	样本量：	20
Group：	MSC combination therapy group	Sample size：	20
干预措施：	静脉滴注+粘膜下注射MSCs	干预措施代码：
Intervention：	MSCs were injected intravenously and submucosal	Intervention code：

组别：	溶液对照组	样本量：	20
Group：	Solution control group	Sample size：	20
干预措施：	静脉滴注+粘膜下注射MSCs所用的溶剂	干预措施代码：
Intervention：	Intravenous infusion and submucosal injection of the solvent used to dissolve MSCs	Intervention code：

组别：	药物对照组	样本量：	20
Group：	Drug control group	Sample size：	20
干预措施：	常用药物治疗	干预措施代码：
Intervention：	Common drug therapy	Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：	中国	省(直辖市)：	上海市	市(区县)：
Country：	China	Province：	Shanghai	City：
单位(医院)：	上海市东方医院	单位级别：	三级甲等医院
Institution hospital：	Shanghai East Hospital	Level of the institution：	Tertiary A Hospital

测量指标：

Outcomes：

指标中文名：	克罗恩病活动指数评分	指标类型：	主要指标
Outcome：	Crohn's Disease Activity Index score	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	克罗恩病简化内镜评分	指标类型：	次要指标
Outcome：	Simplified endoscopy score for Crohn's disease	Type：	Secondary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	C-反应蛋白	指标类型：	次要指标
Outcome：	CRP	Type：	Secondary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	粪便钙卫蛋白水平	指标类型：	次要指标
Outcome：	Fecal calprotectin levels	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：
Sample Name：	Fecal calprotectin levels	Tissue：
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：	粪便	组织：
Sample Name：	Stool	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	18	岁 years
最大 Max age	75	岁 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）：

MSCs治疗组和上述2种对照组的选择采用最小随机化原理实施中央随机化分组。参加本试验的研究人员在筛选出每一例合格受试者后，登录随机系统，填写筛选资料，获取随机号及相应治疗方案进行试验。

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

The MSCs treatment group and the two control groups were selected using the minimum randomization principle to implement central randomization. After selecting each eligible subject, the researchers participating in this trial logged into the random system, filled in the screening data, and obtained the random number.

是否公开试验完成后的统计结果:

Calculated Results after the Study Completed public access:

不公开/Private

盲法：	未说明
Blinding：	Not stated

是否共享原始数据： IPD sharing	否No
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）：	临床试验公共管理平台, http://www.medresman.org.cn
The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：	ResMan, http://www.medresman.org.cn
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：	CRF
Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：	CRF
数据与安全监察委员会： Data and Safety Monitoring Committee：	有/Yes
注册人： Name of Registration：	2020-11-25 06:17:08