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一项单中心、随机、双盲、安慰剂对照、剂量探索评估在健康受试者中皮内注射DNA疫苗INO-4800并进行电脉冲的安全性、耐受性和免疫原性的I期临床研究
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注册号:

Registration number:

ChiCTR2000038152 

最近更新日期:

Date of Last Refreshed on:

2021-01-20 

注册时间:

Date of Registration:

2020-09-11 

注册号状态:

预注册  

Registration Status:

Prospective registration  

注册题目:

一项单中心、随机、双盲、安慰剂对照、剂量探索评估在健康受试者中皮内注射DNA疫苗INO-4800并进行电脉冲的安全性、耐受性和免疫原性的I期临床研究 

Public title:

A Single-center, Randomized, Double-blind, Placebo-controlled, Dose Ranging Phase I Study to Evaluate the Safety, Tolerability, and Immunogenicity of INO-4800, Administered Intradermally Followed by Electroporation in Healthy Volunteers 

注册题目简写:

 

English Acronym:

 

研究课题的正式科学名称:

一项单中心、随机、双盲、安慰剂对照、剂量探索评估在健康受试者中皮内注射DNA疫苗INO-4800并进行电脉冲的安全性、耐受性和免疫原性的I期临床研究 

Scientific title:

A Single-center, Randomized, Double-blind, Placebo-controlled, Dose Ranging Phase I Study to Evaluate the Safety, Tolerability, and Immunogenicity of INO-4800, Administered Intradermally Followed by Electroporation in Healthy Volunteers 

研究课题代号(代码):

Study subject ID:

INO-4800 

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:

怀雪芬 

研究负责人:

张菁 

Applicant:

Xue Fenhuai 

Study leader:

Jing Zhang 

申请注册联系人电话:

Applicant telephone:

+86 18351991682 

研究负责人电话:

Study leader's telephone:

+86 13816357098 

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:

xuefenhuai@advaccine.com 

研究负责人电子邮件:

Study leader's E-mail:

zhanggj61@fudan.edu.cn 

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:

苏州工业园区星湖街218号生物纳米园B1栋308 

研究负责人通讯地址:

上海市乌鲁木齐中路12号 

Applicant address:

Room 308, Building B1, 218 Xinghu Street, Suzhou Industrial Park, Suzhou, Jiangsu, China 

Study leader's address:

12 Middle Urumqi Road, Shanghai, China  

申请注册联系人邮政编码:

Applicant postcode:

215000 

研究负责人邮政编码:

Study leader's postcode:

200000 

申请人所在单位:

艾棣维欣(苏州)生物制药有限公司 

Applicant's institution:

Advaccine (Suzhou) Biopharmaceutical Co., Ltd 

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:

SECCR/2020-20-03 

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:

上海市临床研究伦理委员会 

Name of the ethic committee:

Shanghai Ethics Committee for Clinical Research 

伦理委员会批准日期:

Date of approved by ethic committee:

2020-08-10 

伦理委员会联系人:

张红霞 

Contact Name of the ethic committee:

Hongxia Zhang 

伦理委员会联系地址:

上海市徐汇区枫林路380号枫林国际中心A座18层 

Contact Address of the ethic committee:

18th Floor, Building A, 380 Fenglin Road, Xuhui District, Shanghai, China 

伦理委员会联系人电话:

Contact phone of the ethic committee:

+86 21-33676540 

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 Affiliated to 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 

Primary sponsor's address:

12 Middle Urumqi 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):

上海

市(区县):

Country:

China

Province:

Shanghai

City:

单位(医院):

复旦大学附属华山医院

具体地址:

乌鲁木齐中路12号

Institution
hospital:

Huashan Hospital Affiliated to Fudan University

Address:

12 Middle Urumqi Road

经费或物资来源:

申办方资金 

Source(s) of funding:

Sponosor Investment 

研究疾病:

新型冠状病毒肺炎 

Target disease:

Novel Coronavirus Pneumonia (COVID-19) 

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:

I期临床试验 

Study phase:

研究目的:

评估INO-4800在18-59岁健康受试者中的安全性和耐受性; 初步评价INO-4800在18-59岁健康受试者中的体液免疫应答; 探索INO-4800在18-59岁健康受试者中的细胞免疫应答; 探索肠道和口腔微生态、菌群代谢产物与体液免疫应答和细胞免疫应答水平的关系; 探索疫苗免疫过程中外周血单个核细胞(PBMCs)的变化规律; 描述疫苗免疫过程中B细胞受体(BCR)和T细胞受体(TCR)受体库的变化规律。 

Objectives of Study:

Evaluate the tolerability and safety of INO-4800 administered by ID injection followed by EP in healthy adult volunteers Evaluate the humoral immune response of INO-4800 in healthy subjects Evaluate the cell mediated immune response of INO-4800 in healthy subjects aged 18 to 59 Explore the relationship between the metabolites of intestinal and oral microflora with the levels of humoral and cellular immune responses Explore the change of peripheral blood mononuclear cells (PBMCs) during immunization Describe the changes of B cell receptor (BCR) and T cell receptor (TCR) repertoire during vaccine immunization  

药物成份或治疗方案详述:

本研究为一项单中心、随机、双盲、安慰剂对照、剂量探索评估在18-59岁健康受试者中皮内注射DNA疫苗INO-4800(DNA疫苗INO-4800的活性成分为包含编码SARS-CoV-2 Spike蛋白的全长序列的DNA质粒pGX9501)并进行电脉冲的安全性、耐受性和免疫原性的I期临床研究。 本研究共分为三个阶段:筛选期(首次接种疫苗前14天)、疫苗接种期(分别在第0和第28天接种2剂疫苗)、随访期(第0至第365天,或提前退出)。 在经过至多14天的筛选期之后,预计共纳入45例符合入排标准的健康受试者。共3个剂量组(低剂量0.5 mg组,中剂量1.0 mg组和高剂量2.0 mg组),每个剂量组预计入组15例受试者(3例哨兵受试者接种疫苗;9例受试者接种疫苗,3例受试者接种安慰剂)。 

Description for medicine or protocol of treatment in detail:

This is a Single-center, Randomized, Double blinded, Placebo-controlled, Dose Ranging phase I Study to Evaluate the Safety, Tolerability, and Immunogenicity of INO-4800, Administered intradermally Followed by Electroporation in Healthy Volunteers. During the trial, therere three stages including Screening period (14 days prior to dosing), Immunization period (vaccination on day 0 and day 28), and Follow-up period (from day 29 to day 365, or dropout). 45 healthy volunteers who meet the inclusion and exclusion criteria will be enrolled after at most 14 days screening, and evaluated across 3 dose levels (Low dose as 0.5mg, Medium dose as 1.0mg, High dose as 2.0mg), each of which dose levels will includes 15 participants (early 3 of 15 as sentinels having vaccine administrated, 9 of 15 as participants having vaccine administrated and 3 of 15 will have placebo administrated). 

研究设计:

随机平行对照 

Study design:

Parallel 

纳入标准:

1. 男性或女性志愿者,年龄:18~59周岁(含临界值)。 2. 体重:男性≥ 50 kg,女性≥ 45 kg;体重指数(BMI)在18-30 kg/m2范围内(含临界值)。 3. 从签署知情同意书至末次疫苗注射后12个月,有生育能力的女性受试者或伴侣有生育能力的男性受试者同意并能够采取有效的避孕措施,如避免性生活或采用口服避孕药、避孕套、宫内节育器等可靠的避孕措施。 4. 体格检查正常或异常无临床意义。 5. 生命体征(体温、血压、脉搏、呼吸频率)正常,或异常但研究者认为无临床意义。 6. 12导联心电图和临床实验室结果符合以下任一项: 1) 12导联心电图和临床实验室结果在正常参考值范围内; 2) 12导联心电图和临床实验室结果超过正常参考值范围,但在《预防用疫苗临床试验不良事件分级标准指导原则》定义的<1级; 3) 其他12导联心电图和临床实验室结果在正常参考值范围内,或超过正常参考值范围但研究者认为无临床意义(《预防用疫苗临床试验不良事件分级标准指导原则》中不涵盖的指标)。 7. 自愿参加本临床试验,能够正确理解并签署书面知情同意书。 8. 能够配合研究人员,遵守研究方案要求,并按照方案相关程序完成检查;同意在研究期间遵守研究方案规定的生活方式(出国、出差、旅游等限制)。 

Inclusion criteria

1. Male or female volunteers, age: 18-59 years old (including threshold). 2. Body weight: male >= 50 kg, female >= 45 kg; body mass index (BMI) in the range of 18-30 kg / m2 (including critical value). 3. From signing the informed consent form to 12 months after the last vaccine injection, the fertile female subjects or partners with fertile male subjects agreed and could take effective contraceptive measures, such as avoiding sexual life or using oral contraceptives, condoms, intrauterine devices and other reliable contraceptive measures. 4. Subjects with normal or abnormal physical examination without clinical significance. 5. Subjects with normal vital signs (body temperature, blood pressure, pulse, respiratory rate) or abnormal, but the researchers think it has no clinical significance. The results of ECG were consistent with any of the following 12 leads (1) The 12 lead ECG and clinical laboratory results were within the normal reference range; (2) The 12 lead ECG and clinical laboratory results were beyond the normal reference range, but they were < 1 level defined in the guidelines for classification of adverse events in clinical trials of preventive vaccines; (3) Other 12 lead ECG and clinical laboratory results were within or beyond the normal reference value range, but the researchers did not consider them to be clinically significant (indicators not covered in the guidelines for the classification of adverse events in clinical trials of preventive vaccines). 7. The subjects who voluntarily participate in the clinical trial can correctly understand and sign the written informed consent. 8. Be able to cooperate with the research objects, comply with the requirements of the research protocol, and complete the inspection according to the relevant procedures of the program; agree to abide by the lifestyle specified in the research program (restrictions on going abroad, business trip, travel, etc.) during the study period. 

排除标准:

1. 如下新型冠状病毒筛查任一结果阳性需排除: 1) 新冠血清抗体(IgG和IgM)筛查阳性; 2) 肺部CT呈现新冠影像学特征; 3) 鼻咽拭子的RT-PCR核酸检测阳性; 2. HCV抗体、HBsAg、梅毒螺旋体(TP)抗体、HIV抗体阳性或肺结核阳性者(肺部CT或结核感染T细胞检测[QuantiFERON TB]); 3. 既往已经确诊感染SARS、MERS病毒者; 4. 接种疫苗前2周内急性感染者; 5. 有晕针史者; 6. 在计划注射部位20 厘米范围内有金属植入物者; 7. 在计划注射部位存在纹身、瘢痕瘤形成或增生性瘢痕者; 8. 植入心脏起搏器或自动植入式心律转复除颤器(AICD)者; 9. 任何预激综合征及病史者,例如沃夫巴金森怀特症候群(Wolff-Parkinson-White syndrome)综合征; 10. 血妊娠检测阳性的女性受试者,怀孕/哺乳期妇女,或在12个月内有妊娠计划妇女; 11. 患有导致免疫缺陷或免疫抑制的疾病,如先天性免疫缺陷、恶性血液肿瘤(白血病、淋巴瘤)等,进行器官移植和骨髓移植者; 12. 有过敏性疾病患者或过敏体质(如有血管性水肿/神经性水肿或荨麻疹病史)者或酒精过敏者; 13. 既往接种任何疫苗曾出现过严重过敏反应或已知对本品或其制剂成分(DNA质粒、柠檬酸钠等)过敏者; 14. 曾患或现患有具有临床意义的心血管(除药物能控制高血压)、呼吸、肝脏(除轻度脂肪肝)、肾脏、胃肠道(除慢性胃炎)、内分泌、血液学或神经系统疾病,并且能够显著改变药物的吸收、代谢或清除;或在使用 IP期间造成风险;或干扰数据的解释。排除的病症示例包括但不限于:心绞痛、心力衰竭、哮喘、肝炎、肝硬化、肾功能损害、糖尿病、贫血、癫痫、精神分裂症等; 15. 既往有精神病史者; 16. 接种研究疫苗前4周内接受过手术或化疗,或者计划在研究期间进行手术者; 17. 接种研究疫苗前12周内接受过血液制品(如免疫球蛋白)、研究性药物/器械,或者计划在研究期间使用者; 18. 接种研究疫苗前4周内接种过其他疫苗或接种研究疫苗后2个月内有接种其他疫苗计划(计划外的疫苗紧急接种除外); 19. 签署知情同意书前6个月内接受免疫抑制剂治疗,包括: 1) 长期使用(≥7天)口服或胃肠外糖皮质激素(不包括吸入型、局部皮肤和/或含滴眼液的皮质类固醇、低剂量甲氨蝶呤或剂量低于20 mg/天的皮质类固醇); 2) 目前或预期使用缓解病情剂量的抗风湿药(如硫唑嘌呤、环磷酰胺、环孢菌素、甲氨蝶呤)和生物疾病缓解药物如TNF-α抑制剂(如英夫利西单抗、阿达木单抗或依那西普); 3) 其它可能危及受试者安全、可能干扰研究评估或终点评价,或以其他方式影响研究结果的有效性的其他具有临床意义的免疫抑制。 20. 药物滥用史或药物滥用筛查阳性者; 21. 现阶段或既往酗酒者(每周饮酒超过14个标准单位。1标准单位含14g酒精,如360 mL啤酒或45 mL酒精量为40%的烈酒或150 mL葡萄酒),或酒精呼气测试阳性者; 22. 既往每日吸烟多于10支者; 23. 接种研究疫苗前3个月内献血或大量失血超过400mL或研究期间有计划献血者; 24. 脾脏异常或功能性无脾病史; 25. 其它研究者认为有不适合参加研究的其他因素者。 

Exclusion criteria:

1. Patients with any following positive 2019-nCoV screening results should be excluded: (1) Serum antibodies (IgG and IgM) of the new crown were positive; (2) Lung CT showed new coronal imaging features; (3) The results of RT-PCR were positive. 2. HCV antibody, HBsAg, TP antibody, HIV antibody or tuberculosis positive (lung CT or tuberculosis infection T cell test [QuantiFERON TB]). 3. Patients who have been diagnosed with SARS and mers virus in the past. 4. Patients with acute infection within 2 weeks before vaccination. 5. Objects with a history of needle syncope. 6. Objects with metal implants within 20 cm of the planned injection site. 7. Objects with tattoo, scar formation or hypertrophic scar at the planned injection site. 8. Subjects with pacemaker or automatic implantable cardioverter defibrillator (AICD). 9. Patients with any preexcitation syndrome and history, such as Wolff Parkinson white syndrome. 10. Female subjects with positive blood pregnancy test, pregnant / lactating women, or women with pregnancy plan within 12 months. 11. Patients with diseases leading to immune deficiency or immunosuppression, such as congenital immunodeficiency, hematological malignancies (leukemia, lymphoma), etc., who undergo organ transplantation and bone marrow transplantation. 12. Patients with allergic diseases or objects with allergic constitution (such as history of vascular edema / neuroedema or urticaria) or alcohol allergy. 13. Patients who have experienced severe allergic reactions or known allergies to this product or its preparation ingredients (DNA plasmid, sodium citrate, etc.) before vaccination. 14. Patients who have or are suffering from cardiovascular diseases of clinical significance (except that drugs can control hypertension), respiratory, liver (except mild fatty liver), kidney, gastrointestinal (except chronic gastritis), endocrine, hematological or nervous system diseases, and can significantly change the absorption, metabolism or clearance of drugs; or cause risks during the use of IP; or interfere with the interpretation of data. Examples of excluded diseases include but are not limited to: angina pectoris, heart failure, asthma, hepatitis, liver cirrhosis, kidney damage, diabetes, anemia, epilepsy, schizophrenia, etc. 15. Patients with previous psychiatric history. 16. Patients who had received surgery or chemotherapy within 4 weeks before vaccination of the study vaccine, or who planned to have surgery during the study period. 17. Subjects who have received blood products (e.g., immunoglobulin), research drugs / devices, or planned users during the study period within 12 weeks before vaccination. 18. Subjects who have been vaccinated with other vaccines within 4 weeks before the vaccination of the research vaccine or who have been vaccinated with other vaccines within 2 months after inoculation of the research vaccine (except for emergency vaccination of unplanned vaccines). 19. The subjects who received immunosuppressive therapy within 6 months before signing the informed consent form included: (1) Long term use (>= 7 days) of oral or parenteral glucocorticoids (excluding inhaled, topical skin and / or eye drops containing corticosteroids, low-dose methotrexate or corticosteroids with doses less than 20 mg / day). (2) Current or prospective targets of anti rheumatic drugs with remission doses (such as azathioprine, cyclophosphamide, cyclosporin, methotrexate) and biological disease remission drugs such as TNF - α inhibitors (such as infliximab, adalimumab or etanercept); (3) Other immunosuppressions of clinical significance that may endanger the safety of the subjects, interfere with the study evaluation or endpoint evaluation, or otherwise affect the effectiveness of the study results. 20. Drug abuse history or drug abuse screening positive subjects. 21. Current or past alcohol abusers (drinking more than 14 standard units per week. 1 standard unit contains 14g alcohol, such as 360 ml beer or 45 ml strong liquor with 40% alcohol content or 150 ml wine), or those with positive alcohol breath test. 22. Subjects who used to smoke more than 10 cigarettes a day. 23. Subjects who donated blood or lost more than 400ml blood within 3 months before vaccination or planned blood donation during the study period. 24. Patients with abnormal spleen or functional spleen without history of spleen. 25. Subjects with other factors considered by other researchers to be unsuitable for the study. 

研究实施时间:

Study execute time:

From2020-09-09To 2021-09-13 

征募观察对象时间:

Recruiting time:

From2020-09-14To 2021-09-13 

干预措施:

Interventions:

组别:

试验组

样本量:

36

Group:

experimental group

Sample size:

干预措施:

疫苗 INO-4800

干预措施代码:

Intervention:

Vaccine INO-4800

Intervention code:

组别:

对照组

样本量:

9

Group:

control group

Sample size:

干预措施:

安慰剂

干预措施代码:

Intervention:

placebo

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 Affiliated to Fudan University  

Level of the institution:

Tertiary A 

测量指标:

Outcomes:

指标中文名:

体液免疫应答

指标类型:

次要指标 

Outcome:

Humoral immune response

Type:

Secondary indicator 

测量时间点:

测量方法:

抗体滴度

Measure time point of outcome:

Measure method:

antibody titer

指标中文名:

与疫苗相关的所有不良事件的发生状况(包 括发生率、严重程度等)

指标类型:

主要指标 

Outcome:

Incidence of all adverse events related to vaccine (including incidence, severity, etc.)

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:

结束

Completed

年龄范围:

Participant age:

最小 Min age 18 years
最大 Max age 59 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):

由统计师按受试者入组顺序分配随机号 请描述使用何种方法(随机数字表?统计学软件?或其他)产生随机序列。

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

The statistician will assign codes according to the order in which the subjects are enrolled.

盲法:

双盲

Blinding:

Double blind

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

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):

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:

CRF, EDC

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

CRF, EDC

数据与安全监察委员会:

Data and Safety Monitoring Committee:

有/Yes

注册人:

Name of Registration:

 2020-09-11
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