ChiCTR2100053406 版本V1.0 版本创建时间2021/11/20 19:24:42 中国临床试验注册中心

审核状态:

Project audit state:

通过审核

Successful

注册号:

Registration number:

ChiCTR2100053406 

最近更新时间:

Date of Last Refreshed on:

2021/11/20 19:24:37 

注册号状态:

预注册  

Registration Status:

Prospective registration  

填写语言:

中文和英文  

Language:

Chinese And English  

注册题目:

自体CRISPR-Cas9 编辑的CD34 阳性细胞 (RM-001)治疗输血依赖型β-地中海贫血症安全性和有效性探索 

Public title:

CD34-positive cells edited by autologous CRISPR-Cas9 (RM-001) Treatment of transfusion-dependent β-thalassemia Safety and effectiveness exploration 

注册题目简写:

 

Public title acronym:

 

研究课题的正式科学名称:

自体CRISPR-Cas9 编辑的CD34 阳性细胞 (RM-001)治疗输血依赖型β-地中海贫血症安全性和有效性探索 

Scientific title:

CD34-positive cells edited by autologous CRISPR-Cas9 (RM-001) Treatment of transfusion-dependent β-thalassemia Safety and effectiveness exploration 

研究课题的正式科学名称简写:

 

Scientific title acronym:

 

研究课题代号(代码):

Study subject ID:

IIT-RM-001-01 

在其它机构的注册号:

Secondary ID:

 

申请注册联系人:

刘容容 

研究负责人:

赖永榕 

Applicant:

Liu Rongrong 

Study leader:

Lai Yongrong 

申请注册联系人电话:

Applicant telephone:

+867715356510 

研究负责人电话:

Study leader's telephone:

+867715356510 

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:

liurongrong@stu.gxmu.edu.cn 

研究负责人电子邮件:

Study leader's E-mail:

laiyongrong@hotmail.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:

No. 6 Shuangyong Rd. 

研究负责人通讯地址:

No. 6 Shuangyong Rd. 

Applicant address:

No. 6 Shuangyong Rd., Nanning, Guangxi 

Study leader's address:

No. 6 Shuangyong Rd., Nanning, Guangxi 

申请注册联系人邮政编码:

Applicant postcode:

530021 

研究负责人邮政编码:

Study leader's postcode:

530021 

申请人所在单位:

广西医科大学第一附属医院 

Applicant's institution:

the First Affiliated Hospital, Guangxi Medical 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:

会审2021第(010)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:

广西医科大学第一附属医院医学伦理委员会 

Name of the ethic committee:

Ethical Review Committee, the First Affiliated Hospital of Guangxi Medical University  

伦理委员会批准日期:

Date of approved by ethic committee:

2021-06-24 

国家FDA批准文号:

Approved No. of SFDA:

中国

国家FDA批准附件:

Approved file of SFDA:

国家FDA批准日期:

Date of approved by SFDA:

研究实施负责(组长)单位:

广西医科大学第一附属医院 

Primary sponsor:

the First Affiliated Hospital, Guangxi Medical University  

研究实施负责(组长)单位地址:

广西南宁市青秀区双拥路6号 

Primary sponsor's address:

No. 6 Shuangyong Rd., Nanning, Guangxi 

试验主办单位(项目批准或申办者):

Secondary sponsor:

国家:

中国

省(直辖市):

广西

市(区县):

南宁

Country:

China

Province:

Guangxi

City:

Nanning

单位(医院):

广西医科大学第一附属医院

具体地址:

双拥路6号

Institution
hospital:

the First Affiliated Hospital of Guangxi Medical University

Address:

6 Shuangyong Road

经费或物资来源:

广州瑞风生物科技有限公司 

Source(s) of funding:

Guangzhou Reforgene Medicine Co., Ltd.  

研究疾病:

输血依赖性地中海贫血 

Target disease:

transfusion-dependent β-thalassemia 

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:

探索性研究/预试验 

Study phase:

研究目的:

初步探索自体CRISPR-Cas9编辑的CD34阳性细胞(RM-001)用于输血依赖型β地中海贫血症的安全性及有效性 

Objectives of Study:

Preliminary exploration of the safety and effectiveness of autologous CRISPR-Cas9-edited CD34-positive cells (RM-001) for transfusion-dependent β-thalassemia. 

研究设计:

单臂 

Study design:

Single arm 

纳入标准:

1.患者自愿签署知情同意书(成人或法定代理人)并能完成研究程序和随访检查与治疗; 2.年龄6周岁~35周岁,性别不限; 3.每年输血>100ml/kg,或者在入组前两年每年输血>8次; 4.输血前的报告基线Hb浓度≤7/dL; 5.临床稳定,Karnofsky performance ≥60,适合接受HSCT; 6.具有合适的器官功能,需符合以下标准: ? 天冬氨酸氨基转移酶(AST)≤3倍正常值上限(upper limitof normal,ULN); ? 丙氨酸氨基转移酶(ALT)≤ 3倍ULN; ? 总血清胆红素≤ 2倍ULN,除非合并有Gilbert综合征;总胆红素≤ 3倍ULN且直接胆红素≤1.5倍ULN 的Gilbert综合征患者可以纳入。 ? 血清肌酐≤ 1.5倍ULN,或者肌酐清除率≥ 60mL/min(Cockcroft and Gault 公式); ? 具备最低水平肺储备,定义为≤ 1级呼吸困难且非吸氧状态的血氧饱和度>91%; ? 国际标准化比率(INR)≤1.5倍ULN,且活化部分凝血酶原时间(aPTT)≤1.5倍ULN; 7.具备单个核细胞采集的血管条件; 8.育龄期妇女在RM-001 输注前7 天内的血/尿妊娠试验为阴性,任何有生育能力的男性和女性患者必须同意在整个研究过程中以及研究治疗给药后至少半年内使用有效的避孕方法。根据研究者的判断,患者有生育能力是指:他/她生物学上有能力有孩子以及有正常的性生活。没有生育能力的女性患者(即,满足至少1条以下标准): ? 已行子宫切除术或双侧卵巢切除术,或 ? 经医学确认卵巢衰竭,或 ? 医学确认为绝经后(至少连续12 个月停经)。 

Inclusion criteria

1. The patient voluntarily signs the informed consent form (adult or legal representative) and can complete the research procedures and follow-up inspection and treatment; 2. Age 6~35 years old, no gender limit; 3. Annual blood transfusion>100ml/kg, or blood transfusion>8 times per year in the first two years of enrollment; 4. Report baseline Hb concentration before blood transfusion ≤7/dL; 5. Clinically stable, Karnofsky performance ≥60, suitable for HSCT; 6. With proper organ function, it must meet the following standards: ? Aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal (ULN); ? Alanine aminotransferase (ALT) ≤ 3 times ULN; ? Total serum bilirubin ≤ 2 times ULN, unless combined with Gilbert syndrome; Gilbert syndrome patients with total bilirubin ≤ 3 times ULN and direct bilirubin ≤ 1.5 times ULN can be included. ? Serum creatinine ≤ 1.5 times ULN, or creatinine clearance ≥ 60 mL/min (Cockcroft and Gault formula); ? Possess a minimum level of lung reserve, defined as ≤1 grade dyspnea and blood oxygen saturation in a non-oxygen state >91%; ? International normalized ratio (INR) ≤ 1.5 times ULN, and activated partial prothrombin time (aPTT) ≤ 1.5 times ULN; 7. Have the blood vessel conditions for mononuclear cell collection; 8. Women of childbearing age have a negative blood/urine pregnancy test within 7 days before RM-001 infusion, and any male and female patients with fertility must agree to be effective during the entire study process and at least six months after the administration of the study treatment Method of contraception. According to the judgment of the investigator, the fertility of a patient means that he/she is biologically capable of having children and having a normal sex life. Female patients who are infertile (ie, meet at least one of the following criteria): ? Hysterectomy or bilateral oophorectomy has been performed, or ? Medically confirmed ovarian failure, or ? Medically confirmed as postmenopausal (at least 12 consecutive months of menopause). 

排除标准:

1. 如下病毒检测呈阳性患者:HIV-1/2、HTLV、HCMV、EB、COVID-19。乙肝表面抗原(HBsAg)阳性、乙肝e 抗原(HBeAg)阳性、乙肝e抗体(HBeAb)阳性、乙肝核心抗体(HBcAb)阳性、丙肝抗体(HCV-Ab)阳性、抗梅毒螺旋体抗体(TP-Ab)阳性,符合其中一项者。 2. 筛选时有未控制的活动性感染(例如败血症、菌血症、真菌血症、病毒血症等); 3. 非脾脏功能亢进导致的血小板数<100x109; 4. 凝血功能异常; 5. 晚期肝脏病变。表现为基线丙氨酸转氨酶或胆红素值超过3 倍正常值,或者表现为肝脏活检提示肝硬化、往肝纤维化发展或肝炎。 6. 曾接受过异基因造血干细胞移植(allo-HSCT)的患者。 7. 患者心脏符合以下任何一种情况: ? 左心室射血分数(LVEF)≤45%(ECHO); ? 纽约心脏协会(NYHA)III 或IV 级充血性心力衰竭; ? 需要治疗的严重心律失常,包括QTc 间期男性≥450ms、女性≥470ms(QTcB=QT/RR1/2); ? 未得到控制的高血压(收缩压≥140mmHg和/或舒张压≥90mmHg)或肺动脉高压或不稳定型心绞痛; ? 给药前12个月内有过心肌梗死或搭桥、支架手术; ? 有临床意义的瓣膜病; ? 其他经研究者判断不适合入组的心脏疾病。 8. 经过Hb修正或肺泡体积修正后,预测的CO扩散力(DLco)<50%。 9. MRI表明心脏T2* > 10ms。 10. MRI表明肝脏T2* > 1.4ms。 11. 铁过载,血清铁蛋白超过5000ng/ml。 12. 显著的肺动脉高压,需要药物治疗或者需要输氧。 13. 在入排筛选期的30天内,参与其他临床研究。 14. 已知对试验中所用制剂成分有超敏反应史者。 15. 筛选前6周内接种过活疫苗。 16. 现患或有中枢神经系统疾病史的患者,如癫痫发作、脑血管缺血/出血、瘫痪、失语、中风、严重脑损伤、痴呆、帕金森病、小脑疾病、脑器质性综合征、精神疾病或任何伴累及中枢神经系统的自身免疫性疾病。 17. 曾患有或正患有恶性肿瘤、髓系异常增生或免疫缺陷疾病。既往有恶性肿瘤史,疾病已治愈≥5年的患者可以入选。 18. 直系亲属具有或怀疑具有遗传性癌症(例如,遗传性乳腺癌、遗传性非息肉结直肠癌)。 19. 已知患者患有系统性血管炎(例如Wegener 肉芽肿、结节性多动脉炎)、系统性红斑狼疮、合并活动性或未经控制的自身免疫性疾病(例如Crohns病、类风湿关节炎、自身免疫性溶血性贫血等)、原发性或者继发性免疫缺陷(例如HIV 感染或者严重感染性疾病等)。 20. 为怀孕、哺乳的女性;在移植成功后1年内,不愿意进行避孕的男性或女性。 21. 研究者认为不适合参加本临床试验的其他情况。 

Exclusion criteria:

1. Patients who have tested positive for the following viruses: HIV-1/2, HTLV, HCMV, EB, COVID-19. Hepatitis B surface antigen (HBsAg) positive, hepatitis B e antigen (HBeAg) positive, hepatitis B e antibody (HBeAb) positive, hepatitis B core antibody (HBcAb) positive, hepatitis C antibody (HCV-Ab) positive, anti-Treponema pallidum antibody (TP-Ab) Positive, meet one of them. 2. Uncontrolled active infections during screening (such as sepsis, bacteremia, fungemia, viremia, etc.); 3. The number of platelets not caused by hypersplenic function <100x109; 4. Abnormal blood clotting function; 5. Late liver disease. It is manifested as a baseline alanine aminotransferase or bilirubin value that exceeds 3 times the normal value, or it is manifested as a liver biopsy that indicates cirrhosis, progression to liver fibrosis, or hepatitis. 6. Patients who have received allogeneic hematopoietic stem cell transplantation (allo-HSCT). 7. The patient's heart meets any of the following conditions: ? Left ventricular ejection fraction (LVEF) ≤ 45% (ECHO); ? New York Heart Association (NYHA) grade III or IV congestive heart failure; ? Severe arrhythmia that needs treatment, including QTc interval ≥450ms for males and ≥470ms for females (QTcB=QT/RR1/2); ? Uncontrolled hypertension (systolic blood pressure ≥140mmHg and/or diastolic blood pressure ≥90mmHg) or pulmonary hypertension or unstable angina; ? Have had myocardial infarction or bypass or stent surgery within 12 months before the administration; ? Valvular disease with clinical significance; ? Other heart diseases that the investigator judges are not suitable for inclusion in the group. 8. After Hb correction or alveolar volume correction, the predicted CO diffusion force (DLco) is less than 50%. 9. MRI showed that the heart T2*> 10ms. 10. MRI showed liver T2*> 1.4ms. 11. Iron overload, serum ferritin exceeds 5000ng/ml. 12. Significant pulmonary hypertension requires medication or oxygen. 13. Participate in other clinical studies within 30 days of the screening period. 14. Those who are known to have a history of hypersensitivity to the ingredients of the preparation used in the test. 15. Live vaccines have been vaccinated within 6 weeks before screening. 16. Patients with current or history of central nervous system diseases, such as seizures, cerebrovascular ischemia/hemorrhage, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, cerebral organic syndrome , Mental illness or any autoimmune disease involving the central nervous system. 17. Have had or are suffering from malignant tumors, myeloid hyperplasia or immunodeficiency diseases. Patients who have a history of malignant tumors and have been cured for more than 5 years can be selected. 18. An immediate family member has or is suspected of having hereditary cancer (for example, hereditary breast cancer, hereditary non-polyposis colorectal cancer). 19. Patients are known to have systemic vasculitis (such as Wegeners granulomatosis, polyarteritis nodosa), systemic lupus erythematosus, combined with active or uncontrolled autoimmune diseases (such as Crohns disease, rheumatoid arthritis) Inflammation, autoimmune hemolytic anemia, etc.), primary or secondary immunodeficiency (such as HIV infection or severe infectious diseases, etc.). 20. Women who are pregnant or breast-feeding; men or women who are unwilling to use contraception within 1 year after successful transplantation. 21. Other situations that the investigator believes are not suitable for participating in this clinical trial. 

研究实施时间:

Study execute time:

From2021-11-04To 2024-04-30 

干预措施:

Interventions:

组别:

1组

样本量:

5

Group:

Group 1

Sample size:

干预措施:

静脉注射经CRISPR-Cas9 基因编辑系统体外基因编辑的自体CD34 阳性细胞

干预措施代码:

Intervention:

Intravenous injection of autologous CD34-positive cells gene-edited in vitro by CRISPR-Cas9 gene editing system

Intervention code:

研究实施地点:

Countries of recruitment and research settings:

国家:

中国 

省(直辖市):

广西 

市(区县):

南宁 

Country:

China 

Province:

Guangxi 

City:

Nanning 

单位(医院):

广西医科大学第一附属医院 

单位级别:

三级甲等 

Institution
hospital:

the First Affiliated Hospital of Guangxi Medical University  

Level of the institution:

Tertiary A 

测量指标:

Outcomes:

指标中文名:

胎儿血红蛋白的浓度变化(未输血状态)

指标类型:

主要指标 

Outcome:

Changes in the concentration of fetal hemoglobin (without blood transfusion)

Type:

Primary indicator 

测量时间点:

测量方法:

Measure time point of outcome:

Measure method:

指标中文名:

减少输血(TR12)、摆脱输血依赖(TI12)至少12 个月的比例

指标类型:

主要指标 

Outcome:

Reduce the proportion of blood transfusion (TR12) and get rid of blood transfusion dependence (TI12) for at least 12 months

Type:

Primary indicator 

测量时间点:

测量方法:

Measure time point of outcome:

Measure method:

指标中文名:

外周血淋巴细胞

指标类型:

主要指标 

Outcome:

Peripheral blood lymphocytes

Type:

Primary indicator 

测量时间点:

测量方法:

Measure time point of outcome:

Measure method:

指标中文名:

骨髓细胞中等位基因改变的比例

指标类型:

主要指标 

Outcome:

Proportion of allele changes in bone marrow cells

Type:

Primary indicator 

测量时间点:

测量方法:

Measure time point of outcome:

Measure method:

指标中文名:

生活质量评估

指标类型:

主要指标 

Outcome:

Quality of life assessment

Type:

Primary 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:

Blood

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 6 years
最大 Max age 35 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):

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

N/A

UTN(全球唯一识别码):

盲法:

Blinding:

试验完成后的统计结果:

Calculated Results ater
the Study Completed:

研究负责(组长)单位:

Organizer institution (leader institution):

资料收集汇总单位:

0

Data collection Institution:

资料管理单位:

原始记录保存在医院的HIS系统

Data management Institution:

The original records are kept in the hospital's HIS system

资料分析单位:

原始记录保存在医院的HIS系统,病例报告表采用纸质版本保存在医院档案室

Data analysis Institution:

The original records are kept in the hospital's HIS system, and the case report form made of paper version is kept in the hospital Archives room.

注册人:

Name on Registration:

 2021-11-20