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A Prospective, Randomized, Double-Blind Study of Xiangsha Liujunzi Decotion Compared With Placebo in the First-Line Treatment of Unresectable Hepatocellular Carcinoma

注册号：

Registration number：

ITMCTR2100004340

最近更新日期：

Date of Last Refreshed on：

2020-10-26

注册时间：

Date of Registration：

2020-10-26

注册号状态：

Registration Status：

预注册

Prospective registration

注册题目：

香砂六君子汤对比安慰剂一线治疗不可手术切除肝细胞肝癌的前瞻 性、随机对照、双盲临床研究

Public title：

A Prospective, Randomized, Double-Blind Study of Xiangsha Liujunzi Decotion Compared With Placebo in the First-Line Treatment of Unresectable Hepatocellular Carcinoma

注册题目简写：

English Acronym：

研究课题的正式科学名称：

香砂六君子汤对比安慰剂一线治疗不可手术切除肝细胞肝癌的前瞻 性、随机对照、双盲临床研究

Scientific title：

A Prospective, Randomized, Double-Blind Study of Xiangsha Liujunzi Decotion Compared With Placebo in the First-Line Treatment of Unresectable Hepatocellular Carcinoma

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：

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：

ChiCTR2000039401 ; ChiMCTR2100004340

申请注册联系人：

花永强

研究负责人：

陈震

Applicant：

Yongqiang Hua

Study leader：

Zhen Chen

申请注册联系人电话：

Applicant telephone：

+86 18017317566

研究负责人电话：

Study leader's telephone：

+86 13311965818

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：

keqiang1215@126.com

研究负责人电子邮件：

Study leader's E-mail：

zchenzl@fudan.edu.cn

申请单位网址(自愿提供)：

Study leader's 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：

上海市浦东新区康新公路4333号

研究负责人通讯地址：

上海市徐汇区东安路270号

Applicant address：

4333 Kangxin Road, Pudong New District, Shanghai, China

Study leader's address：

270 Dong'an Road, Xuhui District, Shanghai, 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：

复旦大学附属肿瘤医院

Applicant's institution：

Fudan University Shanghai Cancer Center

是否获伦理委员会批准：

Approved by ethic committee：

伦理委员会批件文号：

Approved No. of ethic committee：

2005217-21

伦理委员会批件附件：

Approved file of Ethical Committee：

View

批准本研究的伦理委员会名称：

复旦大学附属肿瘤医院医学伦理委员会

Name of the ethic committee：

Medical Ethics Committee of Fudan University Cancer Hospital

伦理委员会批准日期：

Date of approved by ethic committee：

2020/5/11 0:00:00

伦理委员会联系人：

张玮静

Contact Name of the ethic committee：

Zhang wei jing

伦理委员会联系地址：

上海市徐汇区东安路270号2号楼5楼伦理办公室

Contact Address of the ethic committee：

Ethics Office, Fifth Floor, Building 2, 270 Dongan Road, Xuhui District, 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：

复旦大学附属肿瘤医院

Primary sponsor：

Fudan University Shanghai Cancer Center

研究实施负责（组长）单位地址：

上海市徐汇区东安路270号

Primary sponsor's address：

270 Dongan Road, Xuhui District, 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(区县)：

Country：

China

Province：

Shanghai

City：

单位(医院)：

复旦大学附属肿瘤医院

具体地址：

徐汇区东安路270号

Institution
hospital：

Shanghai Tumor Hospital

Address：

270 Dongan Road, Xuhui District

经费或物资来源：

上海市“科技创新行动计划”

Source(s) of funding：

Shanghai Science and Technology Innovation Action Plan

研究疾病：

肝细胞癌

研究疾病代码：

Target disease：

Hepatocellular Carcinoma

Target disease code：

研究类型：

Study type：

干预性研究

Interventional study

研究设计：

Study design：

随机平行对照

randomized controlled trial(parallel group design)

研究所处阶段：

Study phase：

探索性研究/预试验

Pilot clinical trial

研究目的：

（1）主要目的 在不能接受根治性手术切除的局部晚期和发生远处转移的肝细胞肝癌受试者中，在接受综合治疗基础上，比较联合香砂六君子汤和联合安慰剂在生活质量和相关中医症候改善方面的差异。 （2）次要目的 比较两组受试者的总生存期，无进展生存时间（PFS）；比较两组采用RECIST标准的客观缓解率（ORR）；比较两组受试者的不良反应，评估方案的安全性。 （3）转化性研究 明确方案在脾虚气滞和非脾虚气滞患者中疗效差异，明确不同证候效果差异，确定作用的目标证候人群；检测血清miRNA，分析表达谱变化与疗效及预后相关性，寻找有效治疗人群标记物，指导临床用药。

Objectives of Study：

1. Main purpose In patients with locally advanced hepatocellular carcinoma (HCC) and distant metastasis who could not accept radical resection, the combination therapy was compared on the basis of comprehensive treatment Objective to investigate the difference between shaliujunzi Decoction and placebo in improving quality of life and related TCM symptoms. 2. Secondary purpose The overall survival and progression free survival (PFS) of the two groups were compared; the objective remission rate (ORR) of the two groups using RECIST standard was compared; the survival time of the two groups was compared The safety of the protocol was evaluated. 3. Translational research To clarify the difference of therapeutic effect between patients with spleen deficiency and qi stagnation and non spleen deficiency and qi stagnation, to identify the effect of different syndromes, to determine the target group of syndromes, and to detect the serum MiRNA, analysis of expression profile changes and curative effect and prognosis, looking for effective treatment population markers, guiding clinical medication.

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] 年龄≥18周岁，男女不限； [2] 符合国家卫计委颁发的《原发性肝癌诊疗规范》（2017版）, 临床诊断标准和／或经过病理组织／细胞学检查确诊的晚期或已经发生转移的HCC患者, 不能够接受肝脏手术，或者手术和／或其他局部治疗后复发进展； [3] 之前未接受过针对晚期或已经发生转移的HCC的一线系统治疗（全身化疗、分子靶向、免疫治疗以及研究治疗用药等），包括但不限于含奥沙利铂的系统化疗、索拉非尼、伦伐替尼、PD-1／PD-L1抗体等； [4] 距肝脏消融或肝动脉介入治疗结束时间>4周，且有关不良反应恢复正常；如果在手术或其他局部治疗后，曾经超越规范进行全身辅助化疗的患者，需化疗结束>6个月，且发生了疾病进展和／或转移； [5] 首次用药前2周内，没有使用具有肝癌适应证的现代中药制剂包括：得力生注射液、康莱特注射液或软胶囊、艾迪或康赛迪注射液、榄香烯注射液／口服液、槐耳颗粒和肝复乐胶囊／片等； [6] 筛选前14天内，未输血或血制品、未使用造血刺激因子、未输白蛋白或血制品； [7] 按照实体瘤反应评估标准（RECIST 1.1），至少具有一个可测量靶病灶，定义为：最长单径≥10mm的非淋巴结病灶，或短径≥15mm的淋巴结病灶；对于既往曾经消融或肝动脉介入等局部治疗后的病灶，必须采用CT／MRI检查并且根据RECIST 1.1标准确定已经发生疾病进展，且最长径≥1.0cm，方可作为可测量的靶病灶； [8] Child-Pugh肝功能评分≤7分； [9] 主要器官功能基本正常，符合下列要求：血小板≥60×10^9／L，血红蛋白≥ 85g／L，白细胞≥3.0×10^9／L；总胆红素≤1.5倍正常值上限（ULN），天冬氨酸转氨酶（AST）和丙氨酸转氨酶(ALT)≤5倍ULN；白蛋白≥ 28g／L；血清肌酐≤1.5倍ULN，或肌酐清除率≥50ml／min； [10] 若HBV-DNA≥104copies／ml(2000IU／ml)，必须先行抗病毒保肝治疗，待HBV-DNA＜104 copies／ml(2000IU／ml)方可入组；并且继续服用抗病毒药物、监测肝功能和乙肝病毒载量； [11] 育龄女性必须在开始治疗前7天内行妊娠试验且结果为阴性；育龄男性：治疗期间及结束后的3个月内采取有效的避孕措施； [12] 受试者自愿加入本研究，签署知情同意书，依从性好，配合随访； [13] 筛选前4周内未参加其他临床试验；如果其他试验筛选失败病例，但是符合本试验要求者可以入组。 [14] 体力状况ECOG评分为0-1； [15] 预期生存时间≥12周；

Inclusion criteria

1. The patients aged 18 years or above are male or female; 2. Patients who meet the criteria for diagnosis and treatment of primary liver cancer (2017 Edition) issued by the national health and Family Planning Commission, and / or patients with advanced or metastatic HCC confirmed by pathology / cytology, are not allowed to undergo liver surgery, or recurrence and progression after surgery and / or other local treatment; 3. Patients who have not received the first-line systemic therapy (systemic chemotherapy, molecular targeting, immunotherapy and research therapy) for advanced or metastatic HCC before, including but not limited to systemic chemotherapy containing oxaliplatin, sorafenib, lenvastinib, PD-1 / PD-L1 antibody, etc.; 4. Patients who are more than 4 weeks away from the end of liver ablation or hepatic artery interventional therapy, and the related adverse reactions return to normal; patients who have gone beyond the standard for systemic adjuvant chemotherapy after surgery or other local treatment, need more than 6 months after the end of chemotherapy, and have disease progression and / or metastasis; 5. Patients who did not use modern Chinese medicine preparations with indications for liver cancer within 2 weeks before the first use of drugs included Delisheng injection, Kanglaite injection or soft capsule, Aidi or Kangsaidi injection, elemene injection / oral liquid, Huaier granule and Ganfule capsule / tablet, etc.; 6. Patients without blood transfusion or blood products, hematopoietic stimulating factor, albumin or blood products within 14 days before screening; 7. According to RECIST 1.1, patients with at least one measurable target lesion were defined as non lymph node lesions with the longest single diameter >= 10 mm, or lymph node lesions with the shortest diameter >= 15 mm. For lesions that had undergone ablation or hepatic artery intervention, CT / MRI examination must be performed, and according to RECIST 1.1 if the disease progression has been confirmed by the standard and the longest diameter is greater than or equal to 1.0 cm, it can be used as the measurable target lesion; 8. Patients with child Pugh liver function score <= 7; 9. Patients with normal function of main organs meet the following requirements: platelets >= 60 x 10^9 / L, hemoglobin >= 85g / L, white blood cells >= 3.0 x 10^9 / L; total bilirubin <= 1.5 times of upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 5 times ULN; albumin >= 28g / L; serum creatinine <= 1.5 times ULN, or creatinine clearance rate >= 50ml / min; 10. If HBV-DNA is more than or equal to 104 copies / ml (2000 IU / ml), antiviral and liver protective therapy must be given first, and only when HBV-DNA is less than or equal to 104 copies / ml (2000 IU / ml) can the patients be enrolled in the group; and antiviral drugs should be taken continuously, liver function and HBV load should be monitored; 11. For women of childbearing age, pregnancy test must be conducted within 7 days before treatment and the result is negative; for men of childbearing age, effective contraceptive measures should be taken during and within 3 months after treatment; 12. The subjects voluntarily joined the study, signed informed consent, good compliance, and cooperated with the follow-up; 13. Subjects who did not participate in other clinical trials within 4 weeks before screening; those who failed in other trials but met the requirements of this trial can be enrolled. 14. Subjects with ECoG score of 0-1; 15. Patients with expected survival time >= 12 weeks.

排除标准：

[1] 影像学检查HCC肝脏肿瘤巨大(≥60%肝体积), 或门脉主干癌栓 (占据血管管径≥50%) , 或癌栓侵犯肠系膜静脉或下腔静脉； [2] 具有临床意义的中等量及以上腹水，即需要治疗性腹腔穿刺／引流, 或者该项指标Child-Pugh评分>2 ； [3] 随机化前28天内接受过局部抗癌治疗（包括手术、消融、肝脏动脉化疗／栓塞或放疗）或大手术； [4] 肝胆管细胞癌和纤维板层细胞癌； [5] 既往5年内或同时存在其他恶性肿瘤癌症，但是原位宫颈癌、曾经治疗的基底细胞癌和浅表膀胱肿瘤(Ta，Tis，T1)除外； [6] 妊娠或哺乳期妇女； [7] 患有CTCAE分级Ⅱ级以上心肌缺血或心肌梗塞、控制不良的心律失常，和／或NYHA标准Ⅲ-Ⅳ级的心功能不全； [8] 之前接受过异体脏器移植，包括肝移植，或者计划在试验期间接受肝移植； [9] 6个月内曾经发生肝性脑病和／或肝性肾病； [10] 活动性丙肝，即抗-HCV阳性或HCV-RNA阳性且肝功能异常者； [11] 人免疫缺陷病毒(HIV)检查结果为阳性，或需要使用抗生素进行全身治疗的严重感染； [12] 无法吞咽、慢性腹泻或肠梗阻，明显影响药物服用和吸收； [13] 6个月之内有消化道出血病史，或者具有明确的胃肠道出血倾向，包括局部活动性溃疡病灶，大便潜血阳性； [14] 患者具有已知活动性或疑诊的自身免疫性疾病； [15] 已知发生中枢神经系统转移，疑有中枢神经系统转移者需进行头颅MRI检查排除； [16] 凝血功能明显异常：国际标准化比值（INR）> 1.5或者凝血酶原时间（PT）> 16 s； [17] 有精神分裂症，或者精神类药物滥用史； [18] 已知对香砂六君子汤成分过敏或不能耐受； [19] 依从性差的患者； [20] 研究者认为妨碍患者参加本试验的其他状况。

Exclusion criteria：

1. Imaging examination of HCC patients with huge liver tumor (>= 60% liver volume), or tumor thrombus in the main portal vein (occupying more than 50% of the vascular diameter), or tumor thrombus invading mesenteric vein or inferior vena cava; 2. Patients with moderate or more ascites of clinical significance need therapeutic abdominal puncture / drainage, or child Pugh score > 2; 3. Patients who received local anticancer therapy (including surgery, ablation, TACE or radiotherapy) or major surgery within 28 days before randomization; 4. Patients with cholangiocarcinoma and fibrolamellar cell carcinoma; 5. Patients with other malignant tumors in the past 5 years or at the same time, except for cervical cancer in situ, basal cell carcinoma and superficial bladder tumor (TA, tis, T1); 6. Pregnant or lactating women; 7. Patients with myocardial ischemia or myocardial infarction of CTCAE grade II or above, poorly controlled arrhythmia, and / or cardiac insufficiency of NYHA grade III-IV; 8. Patients who have received allogeneic organ transplantation before, including liver transplantation, or plan to receive liver transplantation during the trial period; 9. Patients with hepatic encephalopathy and / or hepatic nephropathy within 6 months; 10. Active hepatitis C, that is, patients with anti HCV positive or HCV-RNA positive and abnormal liver function; 11. HIV positive patients or severe infections requiring systemic treatment with antibiotics; 12. The patients who can't swallow, chronic diarrhea or intestinal obstruction obviously affect the drug taking and absorption; 13. Patients with a history of gastrointestinal bleeding within 6 months, or with a clear tendency of gastrointestinal bleeding, including local active ulcer lesions and positive fecal occult blood; 14. The patient has known active or suspected autoimmune diseases; 15. Patients with known central nervous system metastasis should be excluded by MRI; 16. Patients with obvious abnormal coagulation function: international normalized ratio (INR) > 1.5 or prothrombin time (PT) > 16 s; 17. Patients with a history of schizophrenia or psychotropic substance abuse; 18. Patients who are known to be allergic or intolerant to Xiangsha Liujunzi Decoction; 19. Patients with poor compliance; 20. Other conditions considered by the researchers to prevent patients from participating in the trial.

研究实施时间：

Study execute time：

从From 2021-01-01

至To      2022-12-31

征募观察对象时间：

Recruiting time：

从From 2021-01-01

至To      2023-06-30

干预措施：

Interventions：

组别：

安慰剂组

样本量：

60

Group：

Placebo Group

Sample size：

干预措施：

安慰剂

干预措施代码：

Intervention：

Placebo

Intervention code：

组别：

试验组

样本量：

60

Group：

Experimental Group

Sample size：

干预措施：

香砂六君子汤

干预措施代码：

Intervention：

XiangShaLiuJunZi decotion

Intervention code：

样本总量 Total sample size ： 120

研究实施地点：

Countries of recruitment
and research settings：

国家：

中国

省(直辖市)：

上海

市(区县)：

Country：

China

Province：

Shanghai

City：

单位(医院)：

复旦大学附属肿瘤医院

单位级别：

三级甲等

Institution/hospital：

Fudan University Shanghai Cancer Center

Level of the institution：

Tertiary A

测量指标：

Outcomes：

指标中文名：

总生存期

指标类型：

主要指标

Outcome：

overall survival

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

无进展生存时间

指标类型：

主要指标

Outcome：

progression-free survival time

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

不良反应

指标类型：

副作用指标

Outcome：

safety

Type：

Adverse events

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：

objective response rate

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：

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：

正在进行

Recruiting

年龄范围：

最小 18 岁
Min age years
最大 75 岁
Max age years

Recruiting status：

Participant age：

性别：

Gender：

男女均可

Both

随机方法（请说明由何人用什么方法产生随机序列）：

在入选时，所有受试者由研究护士按顺序指定一个受试者编号。受试者编号由1个唯一的3位数字组成，该号码用于整个研究过程中受试者识别，而不会为任何其他受试者所用。利用分层随机法。

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

At the time of enrollment, all subjects will be assigned a subject number by the study nurse in order. The subject number consists of a unique 3-digit number, which is used for subject identification throughout the study and will not be used by any other subjects. Using stratified random method.

盲法：

双盲

Blinding：

Double blind

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）：

暂未确定 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)：

To be determined

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 和 EDC

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

CRF and EDC

数据管理委员会：

Data Managemen Committee：

暂未确定

Not yet

研究计划书或研究结果报告发表信息
（杂志名称、期、卷、页，时间；或网址）：

Publication information of the protocol/research results report
(name of the journal, volume, issue, pages, time; or website):

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