ChiCTR2300068870 版本V1.0 版本创建时间2023/03/01 17:34:58 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：

 ChiCTR2300068870 

最近更新日期：

Date of Last Refreshed on：

 2023-03-01 17:34:53 

注册时间：

Date of Registration：

 2023-03-01 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

信迪利单抗联合紫杉醇/顺铂（TP）用于局部晚期头颈部鳞状细胞癌新辅助治疗的疗效和安全性的前瞻性真实世界研究

Public title：

Efficacy and safety of sintilimab combined with paclitaxel/cisplatin (TP) as neoadjuvant therapy for locally advanced head and neck squamous cell carcinoma (HNSCC) in a prospective real-world study

注册题目简写：

English Acronym：

研究课题的正式科学名称：

信迪利单抗联合紫杉醇/顺铂（TP）用于局部晚期头颈部鳞状细胞癌新辅助治疗的疗效和安全性的前瞻性真实世界研究

Scientific title：

Efficacy and safety of sintilimab combined with paclitaxel/cisplatin (TP) as neoadjuvant therapy for locally advanced head and neck squamous cell carcinoma (HNSCC) in a prospective real-world study

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：

张松男 

研究负责人：

张松男 

Applicant：

Songnan Zhang 

Study leader：

Songnan Zhang 

申请注册联系人电话：

Applicant telephone：

 15526771553

研究负责人电话：

Study leader's
telephone：

15526771553

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：

 zhangsn21@163.com

研究负责人电子邮件：

Study leader's E-mail：

 zhangsn21@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：

吉林省延吉市局子街1327号

研究负责人通讯地址：

吉林省延吉市局子街1327号

Applicant address：

1327 Juzi Strueet, Yanji City, Jilin Province, China

Study leader's address：

1327 Juzi Strueet, Yanji City, Jilin Province, 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：

延边大学附属医院

Applicant's institution：

Affiliated Hospital of Yanbian University

研究负责人所在单位：

延边大学附属医院

Affiliation of the Leader：

Affiliated Hospital of Yanbian 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：

 延医伦理2022299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：

延边大学附属医院医学伦理委员会

Name of the ethic committee：

Medical Ethics Committee of Yanbian University Affiliated Hospital

伦理委员会批准日期：

Date of approved by ethic committee：

 2023-01-04 00:00:00

伦理委员会联系人：

刘延祥

Contact Name of the ethic committee：

yanxiang.liu

伦理委员会联系地址：

吉林省延吉市局子街1327号

Contact Address of the ethic committee：

1327 Juzi Strueet, Yanji City, Jilin Province, 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：

延边大学附属医院

Primary sponsor：

Affiliated Hospital of Yanbian University

研究实施负责（组长）单位地址：

吉林省延吉市局子街1327号

Primary sponsor's address：

1327 Juzi Strueet, Yanji City, Jilin Province, 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)：

吉林

市(区县)：

延吉

Country：

China

Province：

jilin

City：

yanji

单位(医院)：

延边大学附属医院

具体地址：

吉林省延吉市局子街1327号

Institution
hospital：

Affiliated Hospital of Yanbian University

Address：

1327 Juzi Strueet, Yanji, Jilin, China

经费或物资来源：

自筹

Source(s) of funding：

raised by researchists

研究疾病：

局部晚期头颈部鳞癌  

Target disease：

Locally advanced head and neck squamous cell carcinoma

研究疾病代码：

Target disease code：

研究类型：

观察性研究

Study type：

Observational study

研究所处阶段：

 上市后药物 

Study phase：

4

研究设计：

单臂 

Study design：

Single arm 

研究目的：

主要目的： 评估信迪利单抗联合TP化疗方案用于局部晚期头颈部鳞癌新辅助治疗的主要病理缓解率（MPR）和完全病理缓解率（CPR）； 次要目的： 评估信迪利单抗联合TP化疗方案用于局部晚期头颈部鳞癌新辅助治疗的安全性，客观缓解率（ORR），无疾病生存期（DFS），总生存期（OS）： 探索性目的： 探索潜在预测疗效的生物标志物，包括但不限于肿瘤组织标本中的PD-L1表达、P16表达、TMB水平和T细胞亚群等对疗效及预后的提示作用。  

Objectives of Study：

Main Objectives: To evaluate the major pathological response rate (MPR) and complete pathological response rate (CPR) of sintilimab combined with TP chemotherapy in neoadjuvant therapy for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Secondary objectives: To evaluate the safety, objective response rate (ORR), disease free survival (DFS) and overall survival (OS) of sintilimab combined with TP chemotherapy in the neoadjuvant treatment of locally advanced head and neck squamous cell carcinoma. Exploratory objectives: To explore the potential predictive biomarkers for efficacy, including but not limited to PD-L1 expression, P16 expression, TMB level and T cell subsets in tumor tissue samples

药物成份或治疗方案详述：

本研究是评估信迪利单抗用于局部晚期头颈部鳞癌新辅助治疗的真实世界观察性研究。未经任何治疗的、由研究者评估可手术切除局部晚期的头颈部鳞癌患者，签署知情同意后，经筛选符合入排标准，接受信迪利单抗 200 mg +顺铂25 mg/m2 d1-3+紫杉醇75 mg/m2 IV Q3W 治疗 2 周期后，并在第二次给药后的第3-4周内，接受头颈部鳞癌根治性手术治疗，术后由研究者依患者临床情况及分期采取相应指南推荐的标准辅助治疗。 

Description for medicine or protocol of treatment in detail：

This study is a real-world observational study to evaluate sintilimab as neoadjuvant therapy for locally advanced head and neck squamous cell carcinoma. Patients with previously untreated, resectable locally advanced head and neck squamous cell carcinoma, assessed by investigators, who signed informed consent and were screened and met the inclusion and exclusion criteria, received sintilizumab 200 mg + cisplatin 25 mg/m2 d1-3+ paclitaxel 75 mg/m2 IV Q3W for 2 cycles. Patients underwent radical surgery for head and neck squamous cell carcinoma within 3-4 weeks after the second dose, and postoperative standard adjuvant therapy recommended by the corresponding guidelines was adopted by the investigator according to the patient's clinical condition and stage. 

纳入标准：

1.在实施任何试验相关流程之前，签署书面知情同意；T
2.男或女性≥18 周岁，且≤75 周岁；
3.细胞学或组织学诊断为鳞状细胞癌；根据NCCN第8版分期，根据超声内镜或增强CT / MRI扫描cTNM诊断为cT3-4aN1-3M0，且由研究者评估病灶可切除；
4.根据实体肿瘤疗效评价标准（RECIST 1.1版），至少有一处影像学可测量病灶；
5.同意接受根治性手术治疗的患者；
6.由外科医师评估可手术切除且无手术禁忌的患者；
7.ECOG评分0-1分；
8.预期生存时间>6个月；
9.足够器官功能，受试者需满足如下实验室指标：
1)近14天未使用粒细胞集落刺激因子的情况下，中性粒细胞绝对值（ANC）≥1.5x109/L。
2)近14天未输血的情况下，血小板≥100×109/L。
3)近14天内无输血或使用促红细胞生成素的情况下，血红蛋白>9g/dL；
4)总胆红素≤1.5×正常值上限（ULN）；
5)天门冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）在≤2.5×ULN
6)血肌酐≤1.5×ULN并且肌酐清除率（采用Cockcroft-Gault 公式计算）≥60 ml/min；
7)凝血功能良好，定义为国际标准化比值（INR）或凝血酶原时间（PT）≤1.5倍ULN；
8)甲状腺功能正常，定义为促甲状腺激素（TSH）在正常范围内。如基线TSH超出正常范围，如果总T3（或FT3）及FT4在正常范围内的受试者亦可入组；
9)心肌酶谱在正常范围内（如研究者综合判断为不具有临床意义的单纯实验室异常也允许入组）；
10.对于育龄期女性受试者，应在接受首次研究药物给药（第1周期第1天）之前的3天内接受尿液或血清妊娠试验且结果为阴性。如果尿液妊娠试验结果无法确认为阴性，则要求进行血液妊娠试验。非育龄期女性定义为绝经后至少１年，或进行过手术绝育或子宫切除术；
如存在受孕风险，所有受试者（不论男性或女性）均需在整个治疗期间直至治疗末次研究药物给药后120天（或末次化疗药物给药后180天）内采用年失败率低于1%的避孕措施。

Inclusion criteria

1. Provided written informed consent before performing any trial-related procedures; T
2. Male or female ≥18 years old, and ≤75 years old;
3. Squamous cell carcinoma diagnosed by cytology or histology; According to NCCN 8th edition staging, cTNM was diagnosed as cT3-4aN1-3M0 according to EUS or enhanced CT/MRI scan, and the lesions were resectable as evaluated by the investigator.
4. At least one radiographic measurable lesion according to response evaluation Criteria in Solid Tumors (RECIST, version 1.1);
5. Patients who consented to receive radical surgery;
6. Patients evaluated by the surgeon as resectable and without surgical contraindications;
7.ECOG score 0-1;
8. Expected survival time >6 months;
9. Adequate organ function, subject must meet the following laboratory indicators:
1) absolute neutrophil count (ANC) ≥1.5x109/L without using granulocyte colony-stimulating factor for the past 14 days.
2) platelet count ≥100×109/L without blood transfusion in the past 14 days.
3) hemoglobin >9g/dL in the absence of blood transfusion or erythropoietin use in the past 14 days;
4) Total bilirubin ≤1.5× upper limit of normal value (ULN);
5) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN
6) serum creatinine ≤1.5×ULN and creatinine clearance (calculated by Cockcroft-Gault formula) ≥60 ml/min;
7) good coagulation function, defined as INR or PT ≤1.5 times ULN;
8) Euthyroid, defined as thyroid stimulating hormone (TSH) within the normal range. If the baseline TSH was beyond the normal range, the subjects could be included if the total T3 (or FT3) and FT4 were within the normal range.
9) Myocardial enzymes within the normal range (simple laboratory abnormalities that were judged by the investigators as not clinically significant were also allowed);
10. For women of childbearing age, a negative urine or serum pregnancy test should be performed within 3 days before receiving the first dose of study drug (day 1 of cycle 1). If a urine pregnancy test result could not be confirmed as negative, a blood pregnancy test was requested. Women who were not of reproductive age were defined as those who had been postmenopausal for at least 1 year or had undergone surgical sterilization or hysterectomy.
If there was a risk of pregnancy, all participants (male or female) were required to use contraception with an annualized failure rate of less than 1% for the entire treatment period until 120 days after the last dose of study drug on treatment (or 180 days after the last dose of chemotherapy).

排除标准：

1.首次给药前5年内诊断为头颈部鳞癌之外的其他恶性疾病（不包括经过根治的皮肤基底细胞癌、皮肤鳞状上皮癌、和/或经过根治性切除的原位癌）；
2.当前正在参与干预性临床研究治疗，或在首次给药前4周内接受过其他研究药物或使用过研究器械治疗；
3.既往接受过下列疗法：抗PD-1、抗PD-L1或抗PD-L2药物或者针对另一种刺激或协同抑制T细胞受体（例如，CTLA-4、OX-40、CD137）的药物；
4.首次给药前2周内接受过具有抗肿瘤适应症的中成药或免疫调节作用的药物（包括胸腺肽、干扰素、白介素）系统性全身治疗；
5.首次给药前2年内发生过需要全身性治疗（例如使用缓解疾病药物、糖皮质激素或免疫抑制剂）的活动性自身性免疫疾病。替代疗法（例如甲状腺素、胰岛素或者用于肾上腺或垂体机能不全的生理性糖皮质激素等）不视为全身性治疗；
6.研究首次给药前7天内正在接受全身性糖皮质激素治疗（不包括喷鼻、吸入性或其他途径的局部糖皮质激素）或任何其他形式的免疫抑制疗法；
注：允许使用生理剂量的糖皮质激素（≤10 mg/天的泼尼松或等效药物）；
7.已知异体器官移植（角膜移植除外）或异体造血干细胞移植；
8.已知对本研究药物信迪利单抗活性成分或辅料过敏者;
9.在开始治疗前，尚未从任何干预措施引起的毒性和/或并发症中充分恢复（即，≤1级或达到基线，不包括乏力或脱发）；
10.已知人类免疫缺陷病毒（HIV）感染史（即HIV 1/2抗体阳性）；
11.未经治疗的活动性乙肝（定义为HBsAg阳性同时检测到HBV-DNA拷贝数大于所在研究中心检验科正常值上限）；
注：符合下列标准的乙肝受试者亦可入组：
1)首次给药前HBV病毒载量<1000拷贝/ml（200 IU/ml），受试者应在整个研究化疗药物治疗期间接受抗HBV治疗避免病毒再激活
2)对于抗HBc（+）、HBsAg（-）、抗HBs（-）和HBV病毒载量（-）的受试者，不需要接受预防性抗HBV治疗，但是需要密切监测病毒再激活
12.活动性的HCV感染受试者（HCV抗体阳性且HCV-RNA水平高于检测下限）；
13.首次给药之前（第 1 周期，第 1 天）30 天内接种过活疫苗；
注：允许首次给药前 30 天内接受针对季节性流感的注射用灭活病毒疫苗；但是不允许接受鼻内用药的减毒活流感疫苗。
14.妊娠或哺乳期妇女；
15.存在任何严重或不能控制的全身性疾病，例如：
1)静息心电图在节律、传导或形态上出现有重大且症状严重难以控制的异常，如完全性左束支传导阻滞，Ⅱ度以上心脏传导阻滞，室性心律失常或心房颤动；
2)不稳定型心绞痛，充血性心力衰竭，纽约心脏病协会（NYHA）分级≥ 2 级的慢性心衰；
3)在入选治疗前6个月内发生过任何动脉血栓、栓塞或缺血，如心肌梗死、不稳定型心绞痛、脑血管意外或一过性脑缺血发作等；
4)血压控制不理想（收缩压＞140 mmHg，舒张压＞90 mmHg）；
5)首次给药前1年内存在需要糖皮质激素治疗的非感染性肺炎病史，或当前存在临床活动性间质性肺病；
6)活动性肺结核；
7)存在需要全身性治疗的活动性或未能控制的感染；
8)存在临床活动性憩室炎、腹腔脓肿、胃肠道梗阻；
9)肝脏疾病如肝硬化、失代偿性肝病、急性或慢性活动性肝炎；
10)糖尿病控制不佳（空腹血糖（FBG）＞10mmol/L）；
11)尿常规提示尿蛋白≥++，且证实24小时尿蛋白定量＞1.0 g者；
12)存在精神障碍且无法配合治疗的患者；
有可能干扰试验结果、妨碍受试者全程参与研究的病史或疾病证据、治疗或实验室检查值异常，或研究者认为其他不适合入组的情况研究者认为存在其他潜在风险不适合参加本研究

Exclusion criteria：

1. Malignant diseases other than head and neck squamous cell carcinoma (excluding radical basal cell carcinoma, skin squamous cell carcinoma, and/or radical resection carcinoma in situ) diagnosed within 5 years before the first dose;
2. Are currently participating in an interventional clinical study treatment, or have received another study drug or study device within 4 weeks before the first dose;
3. Previous therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or an agent targeting another T-cell receptor that stimulates or coinhibits it (e.g., CTLA-4, OX-40, CD137);
4. Received anti-tumor indications of Chinese patent medicine or immunomodulatory drugs (including thymosin, interferon, interleukin) systemic treatment within 2 weeks before the first dose;
5. Active autoimmune disease requiring systemic therapy (e.g., disease-modifying agents, glucocorticoids, or immunosuppressive agents) occurred within 2 years before the first dose. Alternative therapies (e.g., thyroxine, insulin, or physiological glucocorticoids for adrenal or pituitary insufficiency) were not considered systemic therapy;
6. Receiving systemic glucocorticoids (excluding topical glucocorticoids by nasal spray, inhalation, or other route) or any other form of immunosuppressive therapy within 7 days before the first study dose;
Note: Physiologic doses of glucocorticoids (<= 10 mg per day of prednisone or equivalent) were allowed.
7. Known allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation;
8. Those who are known to be allergic to the active ingredients or excipients of sintilimab;
9. Has not fully recovered from any intervention-related toxicity and/or complications before starting treatment (i.e., grade ≤1 or baseline, excluding fatigue or alopecia);
10. Known history of human immunodeficiency virus (HIV) infection (i.e., HIV 1/2 antibody positive);
11. Untreated active hepatitis B (defined as both HBsAg positivity and HBV-DNA copies greater than the upper limit of normal in the laboratory at the participating center);
Note: Subjects with hepatitis B who met the following criteria were also eligible for inclusion:
1) Subjects with HBV viral load <1000 copies /ml (200 IU/ml) before the first dose should receive anti-HBV therapy throughout the study chemotherapy to avoid viral reactivation
2) For subjects with anti-HBc (+), HBsAg (-), anti-hbs (-) and HBV viral load (-), prophylactic anti-HBV therapy is not required, but viral reactivation should be closely monitored
12. Active HCV-infected subjects (HCV-antibody positive and HCV-RNA level above the lower limit of detection);
13. A live vaccine dose within 30 days before the first dose (cycle 1, day 1);
Note: Administration of injectable inactivated virus vaccine against seasonal influenza within 30 days before the first dose is allowed; Live, attenuated, intranasal influenza vaccine was not allowed.
14. Pregnant or lactating women;
15. The presence of any serious or uncontrolled systemic illness, such as:
1) significant rhythm, conduction or morphological abnormalities in resting ECG, such as complete left bundle branch block, ≥ Ⅱ degree heart block, ventricular arrhythmia or atrial fibrillation;
2) unstable angina, congestive heart failure, New York Heart Association (NYHA) grade ≥ 2 chronic heart failure;
3) any arterial thrombosis, embolism, or ischemia, such as myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic attack, etc. within 6 months before enrollment;
4) poor blood pressure control (systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg);
5) patients had a history of noninfectious pneumonia requiring glucocorticoid treatment within 1 year before the first dose of glucocorticoid, or current clinically active interstitial lung disease;
6) active pulmonary tuberculosis;
7) presence of active or uncontrolled infection requiring systemic therapy;
8) presence of clinically active diverticulitis, abdominal abscess, or gastrointestinal obstruction;
9) liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis;
10) poorly controlled diabetes (fasting blood glucose (FBG) > 10mmol/L);
11) Urine routine test showed urinary protein ≥++ and confirmed 24-hour urinary protein quantitation > 1.0 g;
12) patients with mental disorders who are unable to cooperate with treatment;
Any medical history or evidence of illness, abnormal treatment or laboratory values, or other conditions that might interfere with the results of the trial or prevent full participation in the study, or any other potential risk that might be considered by the investigator to be inappropriate for enrollment.

研究实施时间：

Study execute time：

从 From 2023-03-01 00:00:00至 To 2025-02-28 00:00:00  

征募观察对象时间：

Recruiting time：

从 From 2023-03-01 00:00:00 至 To 2024-02-29 00:00:00

干预措施：

Interventions：

组别：

观察组

样本量：

 30

Group：

observation group

Sample size：

干预措施：

信迪利单抗:200mg, i.v. , d1, q3w; 顺铂25 mg/m2, i.v. ,d1-3,q3w 紫杉醇 75 mg/m2 , i.v. ,d1,q3w， 术前进行2个疗程后，在第2次给药完成后的第3-4周内由研究者评估进行根治性头颈部鳞癌切除手术

干预措施代码：

Intervention：

Sindillizumab :200mg, i.v., d1, q3w; Cisplatin 25 mg/m2, i.v.,d1-3,q3w Paclitaxel 75 mg/m2, i.v.,d1,q3w, Radical head and neck squamous cell carcinoma resection was evaluated by the investigators at 3-4 weeks after the completion of the second dose after 2 courses of treatment

Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：

 中国

省(直辖市)：

 吉林 

市(区县)：

  

Country：

China

Province：

Jilin

City：

单位(医院)：

 延边大学附属医院 

单位级别：

 三级甲等综合医院 

Institution
hospital：

Affiliated Hospital of Yanbian University

Level of the institution：

Tertiary A

测量指标：

Outcomes：

指标中文名：

主要病理缓解率

指标类型：

主要指标

Outcome：

main pathological remission, MPR

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

完全病理缓解率

指标类型：

主要指标

Outcome：

pathological complete response, pCR

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

客观缓解率

指标类型：

次要指标

Outcome：

overall response rate, ORR

Type：

Secondary indicator

测量时间点：

术前一周

测量方法：

Measure time point of outcome：

within 1 week before surgery ]

Measure method：

指标中文名：

无疾病生存期

指标类型：

次要指标

Outcome：

Disease Free Survival, DFS

Type：

Secondary indicator

测量时间点：

术后

测量方法：

Measure time point of outcome：

after surgery

Measure method：

指标中文名：

总生存期

指标类型：

次要指标

Outcome：

Overall Survival, OS

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：

影像学可测量病灶

组织：

Sample Name：

The lesion can be measured by imaging

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：

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：

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）：

未使用

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

Not used

是否公开试验完成后的统计结果:

Calculated Results after the Study Completed public access:

公开/Public

盲法：

N/A

Blinding：

N/A

试验完成后的统计结果（上传文件）：

Calculated Results after
the Study Completed(upload file)：

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）：

未说明 请阅读网页注册指南中关于 原始数据共享 的内容。

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

Not stated

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：

CRF

数据与安全监察委员会：

Data and Safety Monitoring Committee：

暂未确定/Not yet

注册人：

Name of Registration：

  2023-03-01 17:34:53