ChiCTR2500095477 版本V1.0 版本创建时间2025/01/08 08:48:51 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：

 ChiCTR2500095477 

最近更新日期：

Date of Last Refreshed on：

 2025-01-08 08:48:43 

注册时间：

Date of Registration：

 2025-01-08 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

探究新辅助膀胱内灌注丝裂霉素联合En-Bloc术式治疗高危NMIBC患者的有效性及安全性

Public title：

Investigating the efficacy and safety of intravesical instillation of mitomycin C combined with en-bloc surgery in treating high-risk non-muscle-invasive bladder cancer (NMIBC) patients

注册题目简写：

English Acronym：

研究课题的正式科学名称：

探究新辅助膀胱内灌注丝裂霉素联合En-Bloc术式治疗高危NMIBC患者的有效性及安全性

Scientific title：

Investigating the efficacy and safety of intravesical instillation of mitomycin C combined with en-bloc surgery in treating high-risk non-muscle-invasive bladder cancer (NMIBC) patients

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：

寻阳 

研究负责人：

王少刚 

Applicant：

Yang Xun 

Study leader：

Shaogang Wang 

申请注册联系人电话：

Applicant telephone：

 +86 13006158416

研究负责人电话：

Study leader's
telephone：

+86 13367255851

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：

 tjxyang1993@163.com

研究负责人电子邮件：

Study leader's E-mail：

 sgwangtjm@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：

湖北省武汉市硚口区解放大道1095号

研究负责人通讯地址：

湖北省武汉市硚口区解放大道1095号

Applicant address：

1095 Jiefang Avenue, Qiaokou District, Wuhan City, Hubei Province

Study leader's address：

1095 Jiefang Avenue, Qiaokou District, Wuhan City, Hubei Province

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：

华中科技大学同济医学院附属同济医院

Applicant's institution：

Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

研究负责人所在单位：

华中科技大学同济医学院附属同济医院

Affiliation of the Leader：

Tongji Hospital, Tongji Medical College ,Huazhong University of Science and Technology

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：

 [2024]伦审字(S030)号;[2024]伦审字(S030)号-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：

华中科技大学药物临床试验伦理委员会

Name of the ethic committee：

Clinical Trial Ethics Committee of Huazhong University of Science and Technology

伦理委员会批准日期：

Date of approved by ethic committee：

 2024-02-28 00:00:00

伦理委员会联系人：

徐戎

Contact Name of the ethic committee：

Rong Xu

伦理委员会联系地址：

湖北省武汉市硚口区解放大道1095号

Contact Address of the ethic committee：

1095 Jiefang Avenue, Qiaokou District, Wuhan City, Hubei Province

伦理委员会联系人电话：

Contact phone of the ethic committee：

 +86 27 83691785

伦理委员会联系人邮箱：

Contact email of the ethic committee：

 rongxu@hust.edu.cn

研究实施负责（组长）单位：

华中科技大学同济医学院附属同济医院

Primary sponsor：

Tongji Hospital, Tongji Medical College ,Huazhong University of Science and Technology

研究实施负责（组长）单位地址：

湖北省武汉市硚口区解放大道1095号

Primary sponsor's address：

1095 Jiefang Avenue, Qiaokou District, Wuhan City, Hubei Province

试验主办单位(项目批准或申办者)：

Secondary sponsor：

国家：

中国

省(直辖市)：

湖北

市(区县)：

Country：

China

Province：

Hubei

City：

单位(医院)：

华中科技大学同济医学院附属同济医院

具体地址：

湖北省武汉市硚口区解放大道1095号

Institution
hospital：

Tongji Hospital, Tongji Medical College ,Huazhong University of Science and Technology

Address：

1095 Jiefang Avenue, Qiaokou District, Wuhan City, Hubei Province

经费或物资来源：

同济医院高质量临床研究基金

Source(s) of funding：

High-Quality Clinical Research Fund of Tongji Hospital

研究疾病：

高危非肌层浸润性膀胱癌  

Target disease：

High risk non-muscular invasive bladder cancer

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：

 其它 

Study phase：

N/A

研究设计：

随机平行对照 

Study design：

Parallel 

研究目的：

主要研究目的： 比较高危NMIBC患者应用新辅助膀胱内灌注丝裂霉素联合en-bloc手术与安慰剂联合en-bloc手术的1年无复发生存（RFS）。 次要研究目的： 1.比较高危NMIBC患者应用新辅助膀胱内灌注丝裂霉素联合en-bloc手术与安慰剂联合en-bloc手术的无进展生存期（PFS）。 2.比较高危NMIBC患者应用新辅助膀胱内灌注丝裂霉素联合en-bloc手术与安慰剂联合en-bloc手术的总生存期（OS）。 3.比较高危NMIBC患者应用新辅助膀胱内灌注丝裂霉素联合en-bloc手术与安慰剂联合en-bloc手术的健康相关生活质量（HRQoL）。 4.比较高危NMIBC患者应用新辅助膀胱内灌注丝裂霉素联合en-bloc手术与安慰剂联合en-bloc手术的安全性特征。 探索性研究目的： 1.在新辅助治疗前收集患者的尿液进行UroCAD全基因组测序，探索新辅助膀胱内灌注治疗的有效预测因子。 2.在en-bloc术后每次复查期间留取患者的尿液进行UroCAD全基因组测序，探索经尿液的无创液体活检是否可以早于影像学及膀胱镜等常规复查手段检出患者膀胱癌的复发。  

Objectives of Study：

Main Research Objective: To compare the 1-year recurrence-free survival (RFS) between high-risk non-muscle-invasive bladder cancer (NMIBC) patients treated with neoadjuvant intravesical instillation of mitomycin C combined with en-bloc surgery and those treated with placebo combined with en-bloc surgery. Secondary Research Objectives: 1. To compare the progression-free survival (PFS) and overall survival (OS) of high-risk NMIBC patients who underwent neoassisted intravesical infusion mitomycin combined with en-bloc surgery and placebo combined with en-bloc surgery. 2. To compare the health-related quality of life (HRQoL) of high-risk NMIBC patients undergoing neoassisted intravesical infusion of mitomycin combined with en-bloc surgery and placebo combined with en-bloc surgery. 3. To compare the safety characteristics of neoassisted intravesical infusion of mitomycin combined with en-bloc surgery and placebo combined with en-bloc surgery in high-risk NMIBC patients. Exploratory Research Objectives: 1. To collect patients' urine before neoadjuvant treatment for UroCAD whole-genome sequencing to explore effective predictive factors for neoadjuvant intravesical instillation therapy. 2. To collect patients' urine during each follow-up period after en-bloc surgery for UroCAD whole-genome sequencing to explore whether non-invasive liquid biopsy through urine can detect the recurrence of bladder cancer earlier than conventional follow-up methods such as imaging and cystoscopy

药物成份或治疗方案详述：

 

Description for medicine or protocol of treatment in detail：

 

纳入标准：

1.自愿签署知情同意书，了解本研究并愿意遵循且有能力完成所有试验程序； 2.男女不限，年龄 18~75 周岁（含边界值）； 3.美国东部肿瘤协作组（ECOG）评分体能状态为 0 或 1 的患者； 4.既往经影像学和病理学证实的非肌层浸润性膀胱癌； 5.符合《EAU指南（2024版）》危险分组为高危的NMIBC患者。除极高危组外所有的T1 HG/G3和CIS患者；Ta LG/G2 或T1G1, 非CIS 伴有三个危险因素；Ta HG/G3 或 T1 LG, 非CIS伴有至少两个危险因素；T1G2 非CIS伴有至少一个危险因素。（危险因素：年龄> 70岁;多发乳头状肿瘤;肿瘤直径> 3cm）； 6.受试者愿意提供末次膀胱镜活检标本或前次复发手术的标本（包括石蜡块、石蜡包埋切片等）； 7.既往接受的抗肿瘤治疗（放化疗、免疫治疗）距离本试验首次给药间隔>=6 周； 8.有适宜的器官功能及造血功能：中性粒细胞计数（NEUT>=1.5×109/L；白细胞计数（WBC）>=3.0×109/L；血小板计数>=100×109/L；血红蛋白>=90g/L；血清肌酐<=1.5倍正常值上限（ULN）；AST 和 ALT<=2.5 倍 ULN；血清总胆红素<=1.5 倍 ULN；活化部分凝血活酶时间（APTT）<=1.5 倍ULN（正在接受抗凝治疗的患者除外）； 9.男性受试者必须同意在治疗期间及末次治疗后至少 180 天采取有效的避孕措施，并且在此期间不得捐献精子；育龄妇女，须在首次新辅助灌注前72小时内血妊娠试验阴性，并在治疗期间及en-bloc治疗后至少180天同意采取有效的避孕措施。

Inclusion criteria

1. Voluntarily signed informed consent, understand the study and are willing to follow and have the ability to complete all trial procedures; 2. Male or female, age 18~75 years old (including boundary value); 3. Patients with a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) score; 4. Prior non-muscle-invasive bladder cancer confirmed by imaging and pathology; 5. Patients with NMIBC who meet the EAU Guidelines (2024 Edition) and are classified as high-risk. All patients with T1 HG/G3 and CIS except the very high-risk group; Ta LG/G2 or T1G1, non-CIS with three risk factors; Ta HG/G3 or T1 LG, non-CIS with at least two risk factors; T1G2 non-CIS with at least one risk factor. (Risk factors: age> 70 years; multiple papillary tumors; tumor diameter> 3 cm); 6. Subjects are willing to provide specimens from the last cystoscopic biopsy or specimens from previous recurrent surgery (including paraffin blocks, paraffin-embedded sections, etc.); 7. The interval between the first dose of anti-tumor therapy (chemoradiotherapy, immunotherapy) received in the past is >=6 weeks from the first dose of this trial; 8. Appropriate organ function and hematopoietic function: neutrophil count (NEUT>=1.5×109/L; White blood cell count (WBC) >=3.0×109/L; Platelet count>=100×109/L; hemoglobin > = 90 g/L; serum creatinine < = 1.5 times the upper limit of normal (ULN); AST and ALT<=2.5 times ULN; serum total bilirubin <=1.5 times ULN; Activated partial thromboplastin time (APTT) <=1.5 times ULN (except for patients receiving anticoagulant therapy); 9. Male subjects must agree to use effective contraception during the treatment period and for at least 180 days after the last treatment, and not to donate sperm during this period; Women of childbearing potential must have a negative blood pregnancy test within 72 hours prior to the first neoadjuvant perfusion and agree to use effective contraception during treatment and for at least 180 days after en-bloc treatment.

排除标准：

1.原发肿瘤为上尿路、输尿管尿路上皮癌； 2.入组前 5 年内罹患膀胱尿路上皮癌之外的恶性肿瘤患者。但不包括以下几种病人（以下可入组）： 患有局部低风险的前列腺癌（分期<=T2b，Gleason 评分<=7，且 PSA<=20ng/ml，经治疗后未复发（复查 PSA 水平来判断））； 患有低风险前列腺癌（分期 T1/T2a，Gleason 评分<=7，且 PSA<=10ng/ml， 处于观察但未接受治疗的阶段； 符合其他入组标准，但患有极低转移或死亡风险的恶性肿瘤，经标准治疗 后，复查经影像学及疾病特异性肿瘤标志物检测显示无复发或转移的患者，如充分治疗的原位宫颈癌、基底或鳞状细胞皮肤癌；经治疗手术后的原位导管癌等； 3.患有活动性自身免疫疾病的患者，并在过去两年中需要全身性治疗（即长期使用皮质类固醇或免疫抑制类药物）。替代疗法（如甲状腺素、胰岛素或用于肾 上腺或垂体功能不全的生理性皮质类固醇替代疗法）除外； 4.预计在本研究期间有重大手术或给药前4周内进行过大型手术且未完全恢复的患者； 5.在本研究筛选前，既往癌症治疗所引起的任何免疫相关毒性未恢复至<=1级（正 在接受稳定剂量的激素替代疗法的2级内分泌系统疾病除外），和/或与既往抗癌治疗相关的任何其他毒性（免疫相关毒性除外）未恢复至<=2级，脱发除外； 6.人类免疫缺陷病毒（HIV）血清阳性或有 HIV 感染病史或其他获得性免疫缺陷病； 7.乙肝、丙肝等需要长期服用抗病毒药物的患者，其中，乙型肝炎（需同时满足 HBsAg 阳性，且 HBV DNA>=2000 IU/ml，并排除药物或其他原因所致肝炎），丙型肝炎（需同时满足抗 HCV 抗体阳性，且 HCV-RNA结果大于检查下限）； 8.经治疗未控制稳定的系统性疾病，如心脑血管疾病、糖尿病等； 9.有器官移植史、或干细胞移植史； 10.心功能不全（按照美国纽约心脏病协会 NY-HA 分级为 III-IV 级的患者）； 11.明显的肺部疾病（如休息或轻微活动时呼吸短促或任何原因便需要补氧）； 12.参与研究前经研究者判定患者患有其他基础疾病致使不能使用研究药物或会干扰疾病诊断，或有潜在可能引起严重并发症； 13.给药前合并其他严重感染的情况； 14.酒精依赖者或近一年内有吸毒或药物滥用史； 15.既往有明确的神经或精神障碍史，如癫痫、痴呆，依从性差者，或存在外周神经系统障碍者； 16.妊娠期或哺乳期，或预期在试验期内妊娠或生育； 17.已知对丝裂霉素注射液及相应辅料过敏或不能耐受者； 18.研究者认为由于其他原因不适合参加本试验的患者。

Exclusion criteria：

1. The primary tumor is upper urinary tract and ureteral urothelial carcinoma; 2. Patients with malignancies other than urothelial carcinoma of the bladder within 5 years prior to enrollment. However, the following types of patients are excluded (the following can be enrolled): Patients with locally low-risk prostate cancer (stage<=T2b, Gleason score <=7, and PSA<=20ng/ml, and no recurrence after treatment (judged by rechecking PSA levels)); Have low-risk prostate cancer (stage T1/T2a, Gleason score<=7, and PSA<=10ng/ml, in the stage of observation but not treatment; Patients who meet other enrollment criteria but have malignancies with very low risk of metastasis or death, and after standard treatment, re-examination shows no recurrence or metastasis by imaging and disease-specific tumor marker testing, such as adequately treated cervical cancer in situ, basal or squamous cell skin cancer; Ductal carcinoma in situ after treatment and surgery; 3. Patients with active autoimmune disease who have required systemic therapy (i.e., long-term use of corticosteroids or immunosuppressive drugs) in the past two years. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is excluded; 4. Patients who are expected to have major surgery or major surgery within 4 weeks prior to dosing during this study and have not fully recovered; 5. Prior screening in this study, any immune-related toxicity caused by prior cancer therapy that has not recovered to Grade <=1 (except for Grade 2 endocrine system disease receiving a stable dose of hormone replacement therapy), and/or any other toxicity associated with prior anticancer therapy (except immune-related toxicity) that has not recovered to Grade <=2, except for alopecia; 6. Human immunodeficiency virus (HIV) seropositivity or history of HIV infection or other acquired immunodeficiency diseases; 7. Patients who need to take antiviral drugs for a long time, such as hepatitis B and hepatitis C, among them, hepatitis B (hepatitis B (HBsAg positive and HBV DNA >=2000 IU/ml, and hepatitis caused by drugs or other causes is excluded), hepatitis C (hepatitis must be positive for anti-HCV antibodies at the same time, and the HCV-RNA result is greater than the lower limit of examination); 8. Systemic diseases that are not controlled and stable after treatment, such as cardiovascular and cerebrovascular diseases, diabetes, etc.; 9. History of organ transplantation or stem cell transplantation; 10. Cardiac insufficiency (patients with grade III-IV according to NY-HA classification from the New York Heart Association); 11. Significant lung disease (e.g., shortness of breath at rest or slight activity, or the need for supplemental oxygen for any reason); 12. Before participating in the study, the investigator judged that the patient has other underlying diseases that make it impossible to use the study drug or interfere with the diagnosis of the disease, or has the potential to cause serious complications; 13. Other serious infections before administration; 14. Alcohol-dependent persons or have a history of drug abuse or drug abuse in the past year; 15. Those who have a clear history of neurological or psychiatric disorders in the past, such as epilepsy, dementia, poor compliance, or peripheral nervous system disorders; 16. Pregnant or lactating, or expected to be pregnant or give birth during the trial period; 17. Those who are known to be allergic to mitomycin injection and corresponding excipients or cannot tolerate it; 18. Patients who, in the opinion of the investigator, are not suitable to participate in this trial due to other reasons.

研究实施时间：

Study execute time：

从 From 2024-12-01 00:00:00至 To 2027-06-30 00:00:00  

征募观察对象时间：

Recruiting time：

从 From 2025-01-08 00:00:00 至 To 2026-06-30 00:00:00

干预措施：

Interventions：

组别：

试验组

样本量：

 90

Group：

Experimental group

Sample size：

干预措施：

每例受试者每次强化新辅助膀胱内灌注需要将 40mg 丝裂霉素溶于 50ml 生理盐水中。给药方式：采用术前新辅助膀胱内灌注的方式进行给药，新辅助灌注周期为 2次，于 en-bloc 手术前 1 天和前 4 小时进行新辅助膀胱内灌注。

干预措施代码：

Intervention：

Each subject needs to dissolve 40mg of mitomycin in 50ml of normal saline per intensive neoadjuvant intravesical perfusion. Dosing method: Preoperative neoadjuvant intravesical perfusion is administered in 2 neoadjuvant perfusion cycles, 1 day before and 4 hours before en-bloc surgery.

Intervention code：

组别：

对照组

样本量：

 90

Group：

Control group

Sample size：

干预措施：

每例受试者每次安慰剂对照新辅助膀胱内灌注 50ml 生理盐水。给药方式：采用术前新辅助膀胱内灌注的方式进行给药，新辅助灌注周期为 2次，于 en-bloc 手术前 1 天和前 4 小时进行新辅助膀胱内灌注。

干预措施代码：

Intervention：

Each subject was given 50ml of normal saline intravesical perfusion per placebo control neoadjuvant bladder. Dosing method: Preoperative neoadjuvant intravesical perfusion is administered in 2 neoadjuvant perfusion cycles, 1 day before and 4 hours before en-bloc surgery.

Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：

 中国

省(直辖市)：

 湖北 

市(区县)：

  

Country：

China

Province：

Hubei

City：

单位(医院)：

 华中科技大学同济医学院附属同济医院 

单位级别：

 三级甲等 

Institution
hospital：

Tongji Hospital, Tongji Medical College ,Huazhong University of Science and Technology

Level of the institution：

Tertiary A

国家：

 中国

省(直辖市)：

 湖北 

市(区县)：

  

Country：

China

Province：

Hubei

City：

单位(医院)：

 武汉市中心医院 

单位级别：

 三级甲等 

Institution
hospital：

The Central Hospital of Wuhan

Level of the institution：

Tertiary A

国家：

 中国

省(直辖市)：

 湖北 

市(区县)：

  

Country：

China

Province：

Hubei

City：

单位(医院)：

 襄阳市中心医院 

单位级别：

 三级甲等 

Institution
hospital：

Xiangyang Central Hospital

Level of the institution：

Tertiary A

测量指标：

Outcomes：

指标中文名：

无复发生存率

指标类型：

主要指标

Outcome：

Recurrence-free survival rate

Type：

Primary indicator

测量时间点：

随机化开始后每八周一次，持续一年

测量方法：

Measure time point of outcome：

Every eight weeks after randomization starts for one year

Measure method：

指标中文名：

总生存期

指标类型：

次要指标

Outcome：

Overall survival

Type：

Secondary indicator

测量时间点：

随机化开始后每年一次

测量方法：

Measure time point of outcome：

Once a year after randomization begins

Measure method：

指标中文名：

无进展生存期

指标类型：

次要指标

Outcome：

Progression free survival

Type：

Secondary indicator

测量时间点：

随机化开始后的一年内每八周一次，一年后每年一次

测量方法：

Measure time point of outcome：

Once every eight weeks for one year after randomization begins and once every year after one year

Measure method：

指标中文名：

健康相关生活质量

指标类型：

次要指标

Outcome：

Health-related quality of life

Type：

Secondary indicator

测量时间点：

筛选期；住院期间；出院后一年

测量方法：

Measure time point of outcome：

Screening period; During hospitalization; One year after discharge

Measure method：

指标中文名：

不良事件

指标类型：

次要指标

Outcome：

Adverse event

Type：

Secondary indicator

测量时间点：

每次新辅助膀胱灌注后；住院期间；出院后八周

测量方法：

Measure time point of outcome：

After each neoadjuvant bladder infusion; During hospitalization; Eight weeks after discharge

Measure method：

采集人体标本：

Collecting sample(s)
from participants：

标本中文名：

尿液

组织：

Sample Name：

Urine

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：

尚未开始

Not yet 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）：

借助SAS9.4 统计分析软件，按照1:1的比例产生180例受试者所接受处理（试验组和安慰剂对照组）的随机安排，列出流水号为001~180所对应的治疗分配。

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

Using the SAS 9.4 statistical analysis software, generate a random allocation of treatments (experimental group and placebo control group) for 180 subjects in a 1:1 ratio, and list the treatment assignments corresponding to the serial numbers from 001 to 180.

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：

双盲，对研究参与者和研究者设盲

Blinding：

Double-blind, blinding the study participants and investigators

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）：

无

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

None

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：

数据管理 数据管理计划 根据《药物临床试验数据管理与统计分析的计划和报告指导原则》的要求，依据临床试验方案与数据管理流程，撰写《数据管理计划》。数据管理计划应包含项目数 据管理过程中的人员分工，具体流程与质量要求等。项目执行过程中应依照“数据管 理计划”进行数据管理工作。 数据采集方式 使用临床试验电子数据采集系统（EDC）系统进行数据采集和管理。EDC 系统需符合 FDA 21CFR Part11 及软件验证体系要求；符合临床试验的电子数据采集技术指 导原则及临床试验数据管理工作技术指南。 数据管理过程及质量控制 ? 数据库的设计与发布：数据管理人员根据方案设计病例报告表，数据库设计师根 据病例报告表构建 eCRF 界面，并根据逻辑核查计划配置核查规则。配置完成后，数 据管理人员需对数据库进行用户接受测试（UAT），测试通过并获得申办者的批准后 数据库方可发布使用。 ? 数据库的录入：原始数据由研究中心指定接受过数据录入培训的人员录入至 EDC 中。对于入组的受试者需收集 EDC 中要求的全部数据；对于参加了筛选检查但未入组的受试者，可仅收集知情同意书签署日期、筛选号、人口学资料及排除原因至 EDC 中。 ? 数据 SDV：临床监查员进行 eCRF 数据与源数据的一致性核查，核查过程中发现问 题可通过 EDC 发送人工质疑。 ? 数据审核：数据进入 EDC 后，数据管理人员和医学人员定期审核数据，审核过程 中发现逻辑或医学上的潜在问题可通过 EDC 发送人工质疑。 ? 质疑管理：质疑源自 EDC 逻辑核查产生的系统质疑和临床监查员、数据管理员等 角色发起的人工质疑。录入员需根据数据管理计划中规定的时限及时回复质疑/更新 数据（如需）。如质疑为系统质疑，更新后的数据符合逻辑后将自动关闭；如不符合 逻辑，数据管理员将审核质疑回复内容，并决定关闭质疑或重启质疑。如质疑为人工 质疑，数据管理员、临床监查员等质疑发起人将分别审核本角色发起的质疑，并决定 关闭质疑或重启质疑。重启质疑需要录入员再次回复/更新数据，相关角色需要再次 审核质疑回复/数据更新，直至质疑所述问题解决。 ?医学编码：在本试验中，对不良事件名称等进行编码。编码变量及所使用的编码 词典及版本、编码频率与操作规范严格遵循数据管理计划执行。对于不能编码的字段， 由数据管理员在 EDC 中发送质疑进行解决。所有编码将在数据库锁定前完成。 ? 外部数据传输：项目启动阶段，数据管理员负责起草数据传输说明文件，后续外 部数据的传输格式、内容、频率等根据该说明文件进行传输。 ? 主要研究者签名：临床监查员、数据管理人员、医学人员等应对数据进行审核， 审核中发现的问题通过质疑形式要求得到解决。数据清理完成后，主要研究者确认 eCRF 中录入数据无误后，通过 EDC 进行电子签名。EDC 中的电子签名具有手写签名同 样的法律效力。主要研究者签名后，如发生数据更新，需重新进行签名。 ? 数据库锁定：由申办者负责人、项目经理、医学人员、统计分析人员和数据管理 人员确定所有需要收集进入 EDC 的数据录入完成并清理完毕，全部外部数据/SAE 一 致性比对完成且比对过程中的问题得到解决，医学编码工作全部结束，SDV 工作已全 部完成，PI 签名全部完成后，共同批准数据库锁定申请表，数据管理人员进行数据 库锁定。 ? 数据提交及归档：数据库锁定后，数据管理人员向统计人员提交数据集。并开始 进行数据管理报告的撰写及项目主文件的归档工作。

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

Data Management Data Management Plan In accordance with the requirements of the "Guidelines for Planning and Reporting of Data Management and Statistical Analysis in Clinical Trials of Drugs," the Data Management Plan should be drafted based on the clinical trial protocol and data management processes. The Data Management Plan should include personnel division, specific processes, and quality requirements in the project data management process. Data management work should be carried out according to the "Data Management Plan" during project execution. Data Collection Method Data collection and management are conducted using a Clinical Trial Electronic Data Capture (EDC) system. The EDC system must comply with FDA 21CFR Part11 and software validation system requirements; it must also adhere to the technical guidelines for electronic data capture in clinical trials and the technical guidelines for data management work in clinical trials. Data Management Process and Quality Control Database Design and Release: Data management personnel design the case report form based on the protocol, and database designers construct the eCRF interface based on the case report form, configuring audit rules according to the logical audit plan. After configuration, data management personnel must conduct User Acceptance Testing (UAT) on the database. The database can only be released for use after passing the test and obtaining the sponsor's approval. Database Entry: Original data is entered into the EDC by personnel designated by the research center who have received data entry training. For enrolled subjects, all data required in the EDC must be collected; for subjects who participated in screening but were not enrolled, only the informed consent signature date, screening number, demographic data, and reasons for exclusion need to be collected in the EDC. Data SDV (Source Data Verification): Clinical monitors conduct consistency checks between eCRF data and source data, and any issues found during the verification process can be sent as manual queries through the EDC. Data Review: After data entry into the EDC, data management personnel and medical staff regularly review the data. Potential logical or medical issues found during the review process can be sent as manual queries through the EDC. Query Management: Queries originate from system-generated queries produced by EDC logical checks and manual queries initiated by roles such as clinical monitors and data managers. Data entry personnel must respond to queries/ update data in a timely manner according to the deadlines specified in the Data Management Plan (if required). If the query is a system-generated query, the updated data will automatically close once it conforms to logic; if it does not conform to logic, the data manager will review the query response content and decide to close or reactivate the query. If the query is a manual query, the data manager, clinical monitor, and other initiators will review the queries initiated by their respective roles and decide to close or reactivate the query. Reactivating a query requires the data entry personnel to respond/ update data again, and the relevant roles need to review the query response/data update again until the issues raised by the query are resolved. Medical Coding: In this trial, coding is performed for adverse event names, etc. Coding variables and the dictionaries and versions used, coding frequency, and operational standards strictly follow the Data Management Plan. For fields that cannot be coded, the data manager sends a query in the EDC for resolution. All coding will be completed before database lock. External Data Transfer: During the project initiation phase, the data manager is responsible for drafting the data transfer specification document, and subsequent external data transfers are conducted according to the format, content, and frequency specified in this document. Principal Investigator Signature: Clinical monitors, data management personnel, and medical staff should review the data, and any issues found during the review should be resolved through queries. After data cleaning is completed, the principal investigator confirms that the data entered in the eCRF is correct and then signs electronically through the EDC. Electronic signatures in the EDC have the same legal as handwritten signatures. If data updates occur after the principal investigator signs, the signature must be redone. Database Lock: The database lock is approved by the sponsor's responsible person, project manager, medical personnel, statistical analysts, and data management personnel after confirming that all data to be collected into the EDC has been entered and cleaned, all external data/SAE consistency checks have been completed and any issues during the checks have been resolved, all medical coding work has been completed, all SDV work has been completed, and all PI signatures have been obtained. The data management personnel then lock the database. Data Submission and Archiving: After the database is locked, data management personnel submit the dataset to the statisticians and begin writing the data management report and archiving the project master file.

数据与安全监察委员会：

Data and Safety Monitoring Committee：

无/No

注册人：

Name of Registration：

  2025-01-08 08:48:43