ChiCTR2500096047 版本V1.0 版本创建时间2025/01/16 14:58:55 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：

ChiCTR2500096047 

最近更新日期：

Date of Last Refreshed on：

2025-01-16 14:58:48 

注册时间：

Date of Registration：

2025-01-16 00:00:00 

注册号状态：

补注册

Registration Status：

Retrospective registration

注册题目：

头孢比罗酯钠注射液在拟诊或确诊中枢神经系统感染患者中的药代动力学特征及血脑屏障穿透性研究

Public title：

Pharmacokinetic Characteristics and Blood-Brain Barrier Penetration of Ceftobiprole in Patients with Proposed or Confirmed Central Nervous System Infection

注册题目简写：

English Acronym：

研究课题的正式科学名称：

头孢比罗酯钠注射液在拟诊或确诊中枢神经系统感染患者中的药代动力学特征及血脑屏障穿透性研究

Scientific title：

Pharmacokinetic Characteristics and Blood-Brain Barrier Penetration of Ceftobiprole in Patients with Proposed or Confirmed Central Nervous System Infection

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：

陈壮苗 

研究负责人：

毛颖/张菁 

Applicant：

Chen Zhuangmiao 

Study leader：

Mao Ying/ Zhang Jing  

申请注册联系人电话：

Applicant telephone：

+86 150 1619 5024

研究负责人电话：

Study leader's telephone：

+86 52887926

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：

chenzhuangmiao@999.com.cn

研究负责人电子邮件：

Study leader's E-mail：

zhangj_fudan@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：

广东省深圳市福田区梅林街道凯丰路2号

研究负责人通讯地址：

上海市乌鲁木齐中路12号华山医院

Applicant address：

No.2, Kaifeng Road, Meilin Street, Futian District, Shenzhen, Guangdong, China

Study leader's address：

Huashan Hospital, 12 Urumqi Middle Road, 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：

深圳华润九新药业有限公司

Applicant's institution：

Shenzhen China Resources Gosun Pharmaceuticals Co., Ltd

研究负责人所在单位：

复旦大学附属华山医院

Affiliation of the Leader：

Huashan Hospital, Fudan University

是否获伦理委员会批准：

是/Yes

Approved by ethic committee：

Yes

伦理委员会批件文号：

Approved No. of ethic committee：

(2024)临审第(783)号,(2024)临审第(783)号修正1

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：

复旦大学附属华山医院伦理审查委员会

Name of the ethic committee：

Ethics Review Committee of Huashan Hospital, Fudan University

伦理委员会批准日期：

Date of approved by ethic committee：

2024-06-18 00:00:00

伦理委员会联系人：

复旦大学附属华山医院伦理审查委员会

Contact Name of the ethic committee：

Ethics Review Committee of Huashan Hospital, Fudan University

伦理委员会联系地址：

上海市乌鲁木齐中路12号华山医院

Contact Address of the ethic committee：

Huashan Hospital, 12 Urumqi Middle Road, Shanghai, China

伦理委员会联系人电话：

Contact phone of the ethic committee：

+86 21 5288 8045

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：

复旦大学附属华山医院

Primary sponsor：

Huashan Hospital, Fudan University

研究实施负责（组长）单位地址：

上海市乌鲁木齐中路12号华山医院

Primary sponsor's address：

Huashan Hospital, 12 Urumqi Middle Road, 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)：

广东省

市(区县)：

深圳市

Country：

China

Province：

Guangdong

City：

Shenzhen

单位(医院)：

深圳华润九新药业有限公司

具体地址：

广东省深圳市福田区梅林街道凯丰路2号

Institution
hospital：

Shenzhen China Resources Gosun Pharmaceuticals Co., Ltd

Address：

No.2, Kaifeng Road, Meilin Street, Futian District, Shenzhen, Guangdong, China

经费或物资来源：

深圳华润九新药业有限公司

Source(s) of funding：

Shenzhen China Resources Gosun Pharmaceuticals Co., Ltd

Target disease：

Central Nervous System Infection

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：

0

研究设计：

单臂 

Study design：

Single arm 

研究目的：

主要研究目的： 研究头孢比罗在拟诊或确诊中枢神经系统感染患者中的药代动力学特征及血脑屏障穿透性。 次要研究目的： 考察细菌性脑膜炎/脑室炎的神经外科术后成人患者中应用头孢比罗酯钠后的安全性。 初步评价细菌性脑膜炎/脑室炎的神经外科术后成人患者中应用头孢比罗酯钠后的临床疗效和/或微生物学疗效（如数据允许）。 初步评估血和脑脊液中生物标记物（中枢神经S100蛋白、神经元特异性烯醇化酶NSE等）在头孢比罗酯钠给药前后的变化。  

Objectives of Study：

Main objective: To investigate the pharmacokinetic characteristics and blood-brain barrier penetration of Ceftobiprole in patients with suspected or confirmed central nervous system infection. Secondary objective: To investigate the safety of Ceftobiprole Medocaril Sodium in adult neurosurgical patients with bacterial meningitis/ventriculitis. To preliminarily evaluate the clinical efficacy and/or microbiological efficacy of Ceftobiprole Medocaril Sodium in adult neurosurgical patients with bacterial meningitis/ventriculitis (where data permit). To preliminarily assess the changes of biomarkers (central nervous system S100 protein, neuron-specific enolase NSE, etc.) in blood and cerebrospinal fluid before and after Ceftobiprole Medocaril Sodium administration.

药物成份或治疗方案详述：

 

Description for medicine or protocol of treatment in detail：

 

纳入标准：

受试者须符合下列所有标准方可纳入研究： 1) 在研究开始之前，获得受试者或其法定代理人自愿签署经伦理委员会批准的知情同意书 2) 年龄 18～70 岁，男女不限； 3) 神经外科术后患者； 4) 临床上拟诊或确诊为神经外科术后中枢神经系统感染，且经医生评估可单独使用头孢比罗抗感染的患者（中枢神经系统感染诊断依据详见附录1）； 5) 因病情需要脑脊液持续引流者（包含脑室外引流或腰大池引流等）； 6) 入选前经抗菌治疗超过48小时，但感染症状和体征未缓解，脑脊液培养仍然阳性的患者亦可入组。

Inclusion criteria

Subjects must meet all of the following criteria to be included in the study: Obtain the subject or his/her legal representative voluntarily sign the informed consent form approved by the Ethics Committee before the start of the study; Aged 18 to 70 years, male or female; Patients after neurosurgery; Patients who are clinically suspected or confirmed as having central nervous system infection after neurosurgery and receive Ceftobiprole alone for anti-infection as assessed by the physician (see Appendix 1 for the detailed basis for the diagnosis of central nervous system infection); Patients requiring continuous drainage of cerebrospinal fluid due to disease condition (including external ventricular drainage or lumbar drainage); Patients who have received antimicrobial therapy for more than 48 hours before enrollment, but whose symptoms and signs of infection have not been relieved, and whose cerebrospinal fluid culture remains positive may also be enrolled.

排除标准：

符合以下任一项标准的患者不能纳入研究： 1) 已知或怀疑对活性物质或【成份】项中列出的任何辅料过敏、头孢菌素类抗生素、其他类型β-内酰胺类抗生素（如青霉素、单酰胺菌素或碳青霉烯类）等严重超敏者； 2) 生命体征不平稳或无法留取脑脊液标本； 3) Ommaya 囊等装置在整个治疗过程中估计不能拔除或更换，需永久留置者； 4) 药物无法控制的癫痫持续状态，或可能影响到方案依从性的精神病症， 或自杀危险者； 5) 有酒精滥用史； 6) 有违禁药物滥用史者； 7) 患者脑脊液培养为屎肠球菌或产ESBL的肠杆菌科菌属者； 8) 经医生判断存在单用头孢比罗酯钠无法控制感染者； 9) 中、重度肾功能减退患者，即内生肌酐清除率（CrCL）≤50mL/min； 内生肌酐清除率（男）= (140-年龄)×体重(kg) / [0.818 ×血肌酐值(μmol/L)] 内生肌酐清除率（女）= 内生肌酐清除率（男）× 0.85 10) 肝功能检查异常者：入选前 3 天丙氨酸转氨酶（ALT）或者天门冬氨酸转氨酶（AST）5 倍参考值上限，且入选前 3 天总胆红素2倍参考值上限； 11) 有任何已知的严重影响免疫系统的疾病者，如：人类免疫缺陷毒缺陷病毒（HIV）的感染史；或进展期血液系统的恶性肿瘤；或脾切除等； 12) 女性妊娠期（血或尿妊娠试验阳性者）、哺乳期患者； 13) 研究者认为可能存在增加受试者危险性或干扰临床研究的任何情况； 14) 入选前已参加过本临床研究并使用过研究药物的患者。

Exclusion criteria：

Patients meeting any of the following criteria could not be included in the study: 1) Known or suspected hypersensitivity to active substances or any excipients listed in [Ingredients], cephalosporin antibiotics, other types of β-lactam antibiotics (such as penicillin, monoamides or carbapenems) and other serious hypersensitivity; 2) Unstable vital signs or inability to obtain cerebrospinal fluid samples; 3) Ommaya capsule and other devices are estimated not to be removed or replaced during the whole treatment process, and permanent indwelling is required; 4) Drug can not control status epilepticus, or may affect the compliance of the program mental illness, or suicide risk; 5) History of alcohol abuse; 6) Having a history of illicit drug abuse; 7) Patients with cerebrospinal fluid culture for Enterococcus faecium or ESBL-producing Enterobacteriaceae; 8) According to the doctor 's judgment, Ceftobiprole Medocaril Sodium alone could not control the infection; 9) Patients with moderate and severe renal dysfunction, i.e., endogenous creatinine clearance (CrCL) ≤ 50 mL/min; endogenous creatinine clearance (male) = (140-age) × body weight (kg)/[0.818 × serum creatinine value (μmol/L)] endogenous creatinine clearance (female) = endogenous creatinine clearance (male) × 0.85 10) Abnormal liver function tests: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 5 times the upper limit of the reference value 3 days before enrollment, and total bilirubin 2 times the upper limit of the reference value 3 days before enrollment; 11) Patients with any known disease that seriously affects the immune system, such as: history of human immunodeficiency virus (HIV) infection; or advanced hematological malignancies; or splenectomy; 12) Female pregnancy (blood or urine pregnancy test positive), lactation patients; 13) Any condition that the investigator considers may increase the risk of the subject or interfere with the clinical study; 14) Patients who have participated in this clinical study and used the study drug before inclusion;

研究实施时间：

Study execute time：

从 From 2024-05-10 00:00:00至 To 2026-12-31 00:00:00  

征募观察对象时间：

Recruiting time：

从From 2024-10-28 00:00:00 至 To 2026-08-31 00:00:00  

干预措施：

Interventions：

组别：

1

样本量：

12

Group：

1

Sample size：

干预措施：

PK样本采集： 血样采集时间如下： 1) 首剂给药前-3h 内（空白）或筛选时血样； 2) 首剂给药后 48~72h内，在一个给药间隔内采集6个点：以静脉输注 2 小时为例：采样时间为静脉输注开始后1h（输注中）、静脉输注开始后2h（输注结束即刻）、2.5h（输注结束后 0.5h）、3h（输注结束后 1h）、4h（输注结束后 2h）、6h（输注结束后4h）采集血样。采样时间窗为±5min，若输注时间超过 2 小时按照输注结束后时间采血样。 3) 末剂给药采集5个血样：以静脉输注 2 小时为例：采样时间为静脉输注开始后2h（输注结束即刻）、6h（输注结束后4h）、8h（输注结束后6h）、12h（输注结束后 10h）、24h（输注结束后22h）采集血样。 每次采集血样量为 2mL。 脑脊液采集时间如下： 1) 首剂给药前-3h 内（空白）或筛选时脑脊液样本； 2) 首剂给药后 48~72h内，在采集 PK 血样的同时留取 2ml 脑脊液样本，并分别在静脉输注开始后0~1h、1~2h、2~2.5h、2.5~3h、3~4h、4~6h分段收集脑脊液，测量其体积，留取时间窗为±5min； 3) 末剂给药采集 PK 血样的同时留取 2ml 脑脊液样本，并分别在静脉输注开始后0~2h、2~6h、6~8h、8~12h、12~24h分段收集脑脊液，测量其体积，留取时间窗为±5min； 每次采集脑脊液量为 2mL。 生物标志物样本采集时间如下： 1) 首剂给药前-3h 内（空白）或筛选时采集血样及脑脊液样本的同时采集生物标志物样本； 2) 末剂给药静脉输注开始后24h（输注结束后22h）采集血样及脑脊液样本的同时采集生物标志物样本。 每次采集血样量为 2mL；每次采集脑脊液量为 2mL。

干预措施代码：

Intervention：

Blood samples were collected at the following times: 1) within -3h before the first dose (blank) or at screening; 2) within 48-72h after the first dose, 6 points were collected within one dosing interval: in the case of intravenous infusion for 2 h: sampling time was 1h (during infusion) after the start of intravenous infusion, 2 h (immediately after the end of infusion), 2.5h (0.5h after the end of infusion), 3h (1h after the end of infusion), 4h (2 h after the end of infusion) and 6h (4h after the end of infusion) after the start of intravenous infusion. The sampling window was ± 5 min, and blood samples were collected at the time after the end of infusion if the infusion time exceeded 2 hours. 3) Five blood samples were collected from the last dose: for example, 2 hours after the start of intravenous infusion: sampling time was 2 hours (immediately after the end of infusion), 6 hours (4 hours after the end of infusion), 8 hours (6 hours after the end of infusion), 12 hours (10 hours after the end of infusion), and 24 hours (22 hours after the end of infusion) after the start of intravenous infusion. The volume of blood collected each time was 2 mL. Cerebrospinal fluid collection time was as follows: 1) cerebrospinal fluid samples were collected within -3h before the first dose (blank) or at screening; 2) within 48-72h after the first dose, 2ml cerebrospinal fluid samples were collected at the same time as PK blood samples, and cerebrospinal fluid samples were collected at 0-1h, 1-2h, 2-2.5h, 2.5-3h, 3-4h and 4-6h after the start of intravenous infusion, respectively, and their volumes were measured, with a time window of ± 5 min; 3) 2ml cerebrospinal fluid samples were collected at the same time as PK blood samples collected at the last dose, and cerebrospinal fluid samples were collected at 0-2h, 2-6h, 6-8h, 8-12h and 12-24h after the start of intravenous infusion, respectively, and their volumes were measured, with a time window of ± 5 min; the cerebrospinal fluid volume collected each time was 2 mL. Biomarker samples were collected within 1) -3h before the first dose (blank) or at screening while collecting blood samples and cerebrospinal fluid samples; 2) 24h after the start of intravenous infusion of the last dose (22h after the end of infusion) while collecting blood samples and cerebrospinal fluid samples. The volume of blood collected each time was 2 mL; the volume of cerebrospinal fluid collected each time was 2 mL.

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(区县)：

  

Country：

China 

Province：

Shanghai 

City：

 

单位(医院)：

复旦大学附属华山医院 

单位级别：

三甲 

Institution
hospital：

Huashan Hospital, Fudan University

Level of the institution：

Tertiary A

测量指标：

Outcomes：

指标中文名：

血PK参数：Cmax,ss（稳态时峰浓度）、Cmin,ss（稳态时谷浓度）、Cav,ss（稳态坪浓度）、AUCPlasma 0-6h,ss（稳态时 0-6h 药时曲线下面积），Tmax（达峰时间）、T1/2（消除半衰期）、CLss（稳态清除率）、Vss（稳态分布容积）

指标类型：

主要指标

Outcome：

Blood PK(Pharmacokinetics) parameters: Cmax, ss (maximum concentration at steady state), Cmin, ss (trough concentration at steady state), Cav, ss (plateau concentration at steady state), AUCPlasma 0-6h, ss (area under the concentration-time curve from 0 to 6h at steady state), Tmax (time to maximum concentration), T1/2 (elimination half-life), CLss (clearance at steady state), Vss (volume of distribution at steady state)

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

脑脊液PK参数：Cmax,ss（稳态时峰浓度）、Cmin,ss（稳态时谷浓度）、AUCCSF 0-6h,ss（稳态时 0-6h 药时曲线下面积）、Tmax（达峰时间）、T1/2（消除半衰期）、CLss（稳态清除率）、分段脑脊液排出量和排出率、脑脊液累积排出量和累积排出率。

指标类型：

主要指标

Outcome：

Cerebrospinal fluid PK(Pharmacokinetics) parameters: Cmax, ss(maximum concentration at steady state), Cmin, ss (trough concentration at steady state), AUCCSF 0-6h, ss (area under the concentration-time curve from 0 to 6h at steady state), Tmax (time to maximum concentration), T1/2(elimination half-life), CLss(clearance at steady state), segmented cerebrospinal fluid output and excretion rate, cumulative cerebrospinal fluid output and cumulative excretion rate.

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

穿透性评价：分别计算头孢比罗在不同时间点的脑脊液与同期血浆的药物浓度比值(CCSF,ss /CPlasma,ss)、AUC 比值(AUCCSF 0-8h ,ss/AUCPlasma 0-8h,ss)及药物峰浓度比值 (Cmax-CSF,ss/Cmax-Plasma,ss)，评价头孢比罗500 mg q6h，输注给药达稳态后在脑脊液中的穿透性。

指标类型：

主要指标

Outcome：

Penetration evaluation: The drug concentration ratio (CCSF, ss/CPlasma, ss), AUC ratio (AUCCSF 0-8h, ss/AUC0-8h, ss) and peak drug concentration ratio (Cmax-CSF, ss/Cmax-Plasma, ss) of ceftobiprole in cerebrospinal fluid at different time points were calculated to evaluate the penetration of ceftobiprole 500 mg q6h in cerebrospinal fluid at steady state after infusion.

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

实验室检查、生命体征、12-导联心电图及体格检查等。不良事件、严重不良事件发生率。

指标类型：

次要指标

Outcome：

Laboratory tests, vital signs, 12-lead ECG and physical examination, etc. Incidence of adverse events and serious adverse events.

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

临床疗效评估：早期临床应答、治疗结束时（EOT）临床应答、治愈评估（TOC）以及给予研究药物开始后第28天的全因死亡分析。微生物学疗效评估（如果数据允许）：清除、假定清除、未清除、假定未清除、不确定。

指标类型：

次要指标

Outcome：

Clinical response assessments: analyses of early clinical response, clinical response at end of treatment (EOT), cure assessment (TOC), and all-cause mortality at 28 days after start of study drug administration. Microbiological response assessment (if data allowed): Clear, presumed clear, not clear, presumed not clear, uncertain.

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

血和脑脊液中生物标记物（中枢神经S100蛋白、神经元特异性烯醇化酶NSE等）与脑损伤、头孢比罗脑脊液穿透性的相关性分析。

指标类型：

次要指标

Outcome：

Correlation analysis of biomarkers (central nervous system S100 protein, neuron-specific enolase NSE, etc.) in blood and cerebrospinal fluid with brain injury and cerebrospinal fluid penetration of ceftobiprole.

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：

标本中文名：

脑脊液

组织：

Sample Name：

Cerebrospinal fluid

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 70 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）：

无

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

None

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：

Blinding：

是否共享原始数据：

IPD sharing

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）：

国家生物信息中心 (https://ngdc.cncb.ac.cn/gsub/)

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

China National center for Bioinformation (https://ngdc.cncb.ac.cn/gsub/)

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：

电子采集和管理系统

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

Electronic Data Capture, EDC

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：

  2025-01-16 14:58:48