中国临床试验注册中心 - 世界卫生组织国际临床试验注册平台一级注册机构

注册号： Registration number：	ChiCTR2400086698
最近更新日期： Date of Last Refreshed on：	2024-07-09 10:20:46
注册时间： Date of Registration：	2024-07-09 00:00:00
注册号状态：	预注册
Registration Status：	Prospective registration
注册题目：	托法替布联合糖皮质激素治疗难治性寻常型天疱疮的单中心、单臂、开放标签临床试验研究
Public title：	A Single-Center, Single-Arm, Open-Label Clinical Trial Evaluating the Efficacy of Tofacitinib in Combination with Corticosteroids for the Management of Refractory pemphigus
注册题目简写：
English Acronym：
研究课题的正式科学名称：	托法替布联合糖皮质激素治疗难治性寻常型天疱疮的单中心、单臂、开放标签临床试验研究
Scientific title：	A Single-Center, Single-Arm, Open-Label Clinical Trial Evaluating the Efficacy of Tofacitinib in Combination with Corticosteroids for the Management of Refractory pemphigus
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：	李想	研究负责人：	张名望
Applicant：	Xiang Li	Study leader：	Mingwang Zhang
申请注册联系人电话： Applicant telephone：	+86 173 1214 0813	研究负责人电话： Study leader's telephone：	+86 138 8344 2884
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：	lxi0994@163.com	研究负责人电子邮件： Study leader's E-mail：	mingwangzhang2@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：	中国重庆市沙坪坝区高滩岩正街30号	研究负责人通讯地址：	中国重庆市沙坪坝区高滩岩正街30号
Applicant address：	Gaotanyan Main Street 30, Shapingba District, Chongqing, China	Study leader's address：	Gaotanyan Main Street 30, Shapingba District, Chongqing, 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：	陆军军医大学第一附属医院
Applicant's institution：	The First Affiliated Hospital of Army Military Medical University
研究负责人所在单位：	陆军军医大学第一附属医院
Affiliation of the Leader：	The First Affiliated Hospital of Army Military Medical 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：	(A)KY2024071	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：	中国人民解放军陆军军医大学第一附属医院伦理委员会
Name of the ethic committee：	Ethics Commitee of the First Affiliated Hospital of Army Medical University, PLA
伦理委员会批准日期： Date of approved by ethic committee：	2024-06-05 00:00:00
伦理委员会联系人：	毛青
Contact Name of the ethic committee：	Qing Mao
伦理委员会联系地址：	中国重庆市沙坪坝区高滩岩正街30号
Contact Address of the ethic committee：	Gaotanyan Main Street 30, Shapingba District, Chongqing, China
伦理委员会联系人电话： Contact phone of the ethic committee：	+86 23 6875 4035	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：

陆军军医大学第一附属医院

Primary sponsor：

The First Affiliated Hospital of Army Medical University

研究实施负责（组长）单位地址：

中国重庆市沙坪坝区高滩岩正街30号

Primary sponsor's address：

Gaotanyan Main Street 30, Shapingba District, Chongqing, 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)：	重庆	市(区县)：	沙坪坝
Country：	China	Province：	Chongqing	City：	Shapingba District
单位(医院)：	陆军军医大学第一附属医院	具体地址：	中国重庆市沙坪坝区高滩岩正街30号
Institution hospital：	the First Affiliated Hospital of Army Medical University	Address：	Gaotanyan Main Street 30, Shapingba District, Chongqing, China

经费或物资来源：

重庆市自然基金，项目编号：cstc2021jcyj-msxmX0140

Source(s) of funding：

Chongqing Nature Foundation, Project number: cstc2021jcyj-msxmX0140

研究疾病：

天疱疮

Target disease：

pemphigus

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：

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：

论证托法替布联合糖皮质激素治疗难治性天疱疮的有效性及安全性

Objectives of Study：

To demonstrate the efficacy and safety of Tofacitinib combined with glucocorticoid in the treatment of refractory pemphigus

药物成份或治疗方案详述：

Description for medicine or protocol of treatment in detail：

纳入标准：

Inclusion criteria

1.Between the ages of 18 and 75 (for fertile women and men, effective contraception is required during treatment and for one month after Tofacitinib treatment is stopped).
2.Informed consent has been signed.
3. Bullous pemphigoid has been diagnosed within the last 24 months using the following diagnostic criteria:
1) :Clinical manifestations: ① Loose, tense bullae and large blisters appear on the skin, easily rupturing; ② Persistent erosions form after the rupture of bullae and blisters; ③ Blisters or erosions develop on mucous membranes; ④ Positive Nikolsky sign.
2):Histopathology: Desquamation of epidermal or epithelial cells, forming vesicles and bullae.
3):immunological criteria: ① DIF on the affected area or normal skin around the lesion shows IgG and/or complement deposition in the intercellular spaces of the epidermal (or epithelial) cells; ② IIF detects the presence of anti-intercellular antibodies in the serum; ③ ELISA detects the presence of anti-Dsg1/3 antibodies in the serum.
4. There is significant disease activity, as defined by the following criteria: the Pemphigus Disease Area Index (PDAI) for skin or mucous membrane pemphigus is at least 3 in both areas, and the PDAI is between 15 and 45 (≥ 15 but ≤ 45).
5. According to the "Expert Consensus on Diagnosis and Treatment of Pemphigus Vulgaris (2020)", refractory disease is defined as follows: For patients with pemphigus vulgaris, after 3 weeks of treatment with an adequate dose (1.5g/kg/d, calculated as prednisone) of glucocorticoids, combined or not combined with immunosuppressive agents (including cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, etc.) for 12 weeks, there are still new erythematous plaques or blisters present or the existing skin lesions continue to expand without healing.
6.  The patient's prednisone dose at enrollment was required to be ≤ 1mg/kg/d and maintained at a stable level for a minimum of 2 weeks.

排除标准：

①. 诊断或有证据考虑红斑型天疱疮、副肿瘤性天疱疮、IgA天疱疮、药物性天疱疮以及其他非寻常型天疱疮类自身免疫大疱性疾病。 ②. 对任何研究药物有过敏史。 ③. 妊娠或者哺乳期，或者打算在研究期间怀孕。 ④. 入组前8周内口服过JAK抑制剂，或者既往使用口服JAK抑制剂治疗病情无充分改善。 ⑤. 基本上或完全丧失能力，几乎或完全不能自我照顾，例如卧床不起。 ⑥. 患有未受控制的高血压，在一个星期内反复出现收缩压>160mmHg或舒张压>100mmHg。 ⑦. 在筛查前8周内曾做过任何重大手术，或在研究期间需要做重大手术。 ⑧. 免疫力低下，且经研究者评估后参与该研究有不可接受的风险。 ⑨. 入组前12周内经历过以下任何一项：心肌梗塞、不稳定型心绞痛、卒中或心衰（纽约心功能分级III/IV期）。 ⑩. 有深静脉血栓（deep venous thrombosis，VET）病史，或被认为是VTE的高危人群，有以下2个或2个以上的VTE危险因素： 1）年龄>75岁； 2）BMI>35 kg/m2； 3）目前服用塞来昔布、依托考昔、避孕药或吸烟。 ⑪. 有心血管、呼吸系统、肝脏、胃肠道、内分泌、血液或神经精神方面的病史，或存在任何其他严重的和/或不稳定的疾病，经研究者评估后参与该研究有不可接受的风险或会干扰数据的可靠性。 ⑫. 有淋巴增生性疾病的病史；或有提示可能是淋巴增生性疾病的体征或症状；过去5年内有任何恶性肿瘤(局限性基底细胞癌除外)病史，不论是否接受过治疗。 ⑬. 目前或近期有严重的病毒、细菌、真菌或寄生虫感染，包括但不限于以下情况： 1）入组前12周内有症状的带状疱疹感染； 2）有播散性/复杂性带状疱疹病史（如多皮节受累、眼带状疱疹、中枢神经系统受累，或带状疱疹后神经痛）； 3）入组时正出现单纯疱疹感染； 4）HBV、HCV或HIV的活动性或慢性感染； 5）有活动性肺结核、潜伏结核的证据，或以前有活动性肺结核的证据，且没有接受过正规的治疗； 6）近4周内有严重的感染或者因感染使用静脉抗生素治疗。 ⑭. 有任何严重的伴随性疾病，预计需要使用全身性糖皮质激素。 ⑮. 近12周内接种过或疫苗或者计划在研究期内接种活疫苗。 ⑯. 心电图异常，且经研究者评估后参与该研究有不可接受的风险。 ⑰. 在筛查的实验室检查中出现以下特定的异常情况： 1）ALT或者AST > 2 正常值上限（Upper Limit Of Normal, ULN）； 2）AIP > 2 ULN； 3）TBL > 1.5 ULN； 4）血红蛋白 < 100g/L； 5）白细胞 < 2.5 109/L； 6）中心粒细胞 < 1.2 109/L； 7）淋巴细胞 < 0.75 109/L； 8）血小板 < 100 109/L； 9）肾小球滤过率 < 40 mL/min/1.73cm2； ⑱. 不能或不愿在研究期间完成随访，和/或不愿意遵守研究限制及程序。 ⑲. 目前正在参加任何其他涉及研究性产品的临床研究或任何其他类型的医学研究，这些研究被认为在科学上或医学上与本研究不相容。 ⑳. 未过以下免疫抑制剂或单抗的洗脱期：甲氨蝶呤、硫唑嘌呤、吗替麦考酚酯、环孢素（3月）；利妥昔单抗、环磷酰胺（12月）；免疫球蛋白（12月）。

Exclusion criteria：

①. Diagnosis or evidence of suspected pemphigus vulgaris, paraneoplastic pemphigus, IgA pemphigus, drug-induced pemphigus, and other non-bullous pemphigoid-like autoimmune bullous diseases. ②. There is a documented history of allergic reactions to any investigational drugs. ③. During the period of pregnancy, lactation, or while planning to conceive throughout the study duration. ④. Patients who have taken JAK inhibitors orally within 8 weeks prior to enrollment, or who have not had a sufficient improvement in their condition with previous oral JAK inhibitor treatment. ⑤. Basically or completely disabled, unable to take care of oneself almost or completely, such as bedridden. ⑥. Suffering from uncontrolled hypertension, with recurrent systolic blood pressure > 160mmHg or diastolic blood pressure > 100mmHg within a week. ⑦. Patients who have had any major surgery within 8 weeks of the screening, or require a major surgery during the study period. ⑧. Patients who exhibit low immunity and are considered by the researchers to pose an unacceptable risk for participation in the study. ⑨. Within the 12 weeks prior to enrollment, the patient has experienced any of the following: myocardial infarction, unstable angina, stroke, or heart failure (NYHA functional classification III/IV stage) ⑩. Individuals with a history of deep venous thrombosis (DVT) or who are considered to be at high risk for VTE, with 2 or more of the following VTE risk factors: 1) Age > 75 years; 2) BMI > 35 kg/m2; 3) Currently taking celecoxib, etoricoxib, contraceptive pills, or smoking. ⑪.Patients who have history of cardiovascular, respiratory, liver, gastrointestinal, endocrine, hematological, or neuropsychiatric disease, or any other serious and/or unstable condition. The investigator determines that participation in the study would have unacceptable risks or would compromise the reliability of the data. ⑫. A history of lymphomatous disease; or signs or symptoms suggestive of lymphomatous disease; or any history of malignant tumor (excluding localized basal cell carcinoma) within the past 5 years, regardless of whether treatment has been received. ⑬.Currently or recently have a serious viral, bacterial, fungal, or parasitic infection, including but not limited to the following: 1) A symptomatic herpes zoster infection within the past 12 weeks prior to enrollment; 2) A history of disseminated/complex herpes zoster (such as multi-dermatome involvement, ocular herpes zoster, or central nervous system involvement) or postherpetic neuralgia; 3) A current case of herpesvirus hominis infection at the time of enrollment; 4) Active or chronic infection with HBV, HCV, or HIV; 5) Evidence of active or latent tuberculosis, or previous evidence of active tuberculosis without receiving proper treatment; 6) A serious infection within the past 4 weeks or treatment with intravenous antibiotics for a serious infection. ⑭. Patients who have any serious condition except bullous pemphigoid that expected to require systemic glucocorticoids. ⑮. Have received or are scheduled to receive a live vaccine within the past 12 weeks. ⑯. Patients who have abnormal ECG findings, and after being evaluated by the researcher, it is determined that participation in the study has unacceptable risks. ⑰. The following specific abnormalities were noted on laboratory tests during screening: 1) ALT or AST > 2 times the upper limit of normal (ULN); 2) AIP > 2 times ULN; 3) TBL > 1.5 times ULN; 4) Hemoglobin < 100g/L; 5) White blood cells < 2.5 10^9/L; 6) Central granulocytes < 1.2 10^9/L; 7) Lymphocytes < 0.75 10^9/L; 8) Platelets < 100 10^9/L; 9) Glomerular filtration rate < 40 mL/min/1.73cm^2; ⑱. Patients who cannot or are unwilling to complete follow-up during the study, and/or are unwilling to comply with the study restrictions and procedures. ⑲. The patient is currently participating in any other clinical study involving investigational products or any other type of medical research that is scientifically or medically incompatible with this study. ⑳. No washout period has passed for the following immunosuppressants or monoclonal antibodies: methotrexate, azathioprine, mycophenolate mofetil, cyclosporine (3 months); rituximab, cisplatin (12 months); immunoglobulin (12 months).

研究实施时间：

Study execute time：

从 From 2024-07-15 00:00:00至 To 2025-02-01 00:00:00

征募观察对象时间：

Recruiting time：

从 From 2024-07-15 00:00:00 至 To 2025-02-01 00:00:00

干预措施：

Interventions：

组别：	试验组	样本量：	20
Group：	experimental group	Sample size：	20
干预措施：	给予醋酸泼尼松片1mg/kg/d及托法替布5mg 2/日控制病情。	干预措施代码：
Intervention：	Administered with prednisone acetate at a dosage of 1mg/kg/day and tofacitinib at a dosage of 5mg twice daily for disease control.	Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：	中国	省(直辖市)：	重庆市	市(区县)：
Country：	China	Province：	Chongqing	City：
单位(医院)：	陆军军医大学第一附属医院	单位级别：	三甲
Institution hospital：	the First Affiliated Hospital of Army Medical University	Level of the institution：	Tertiary A

测量指标：

Outcomes：

指标中文名：	在第24周时实现疾病完全缓解的受试者比例	指标类型：	主要指标
Outcome：	The proportion of participants who achieved complete disease remission by week 24	Type：	Primary indicator
测量时间点：	24周	测量方法：	临床观察法
Measure time point of outcome：	24 weeks	Measure method：	Clinical observation method

指标中文名：	第0、2、4、8、12、16、20、24周时受试者PDAI活动度评分改善值	指标类型：	次要指标
Outcome：	The improvement in BPDAI activity scores at weeks 0, 2, 4, 8, 12, 16, 20, and 24 for the participants	Type：	Secondary indicator
测量时间点：	第0、2、4、8、12、16、20、24周	测量方法：	评分表
Measure time point of outcome：	at 0, 2, 4, 8, 12, 16, 20 weeks	Measure method：	rating scale

指标中文名：	受试者从基线至完全缓解所需时间	指标类型：	次要指标
Outcome：	The time it takes for the participant to reach complete remission from the baseline	Type：	Secondary indicator
测量时间点：	24周	测量方法：
Measure time point of outcome：	24 weeks	Measure method：

指标中文名：	治疗期间受试者复发次数	指标类型：	次要指标
Outcome：	The number of recurrences experienced by the participants during the treatment period.	Type：	Secondary indicator
测量时间点：	24周	测量方法：
Measure time point of outcome：	24 weeks	Measure method：

指标中文名：	治疗期间受试者复发时的时间	指标类型：	次要指标
Outcome：	The time of relapse during the course of treatment for the participants.	Type：	Secondary indicator
测量时间点：	24周	测量方法：
Measure time point of outcome：	24 weeks	Measure method：

指标中文名：	治疗期间使用的泼尼松累计剂量	指标类型：	次要指标
Outcome：	The cumulative dose of prednisone used during the course of treatment.	Type：	Secondary indicator
测量时间点：	24周	测量方法：
Measure time point of outcome：	24 weeks	Measure method：

指标中文名：	第0、4、8、12、16、20、24周时受试者Dsg1及Dsg3水平变化	指标类型：	次要指标
Outcome：	The levels of Dsg1 and Dsg3 in the participants changed at weeks 0, 4, 8, 12, 16, 20, and 24.	Type：	Secondary indicator
测量时间点：	24周	测量方法：
Measure time point of outcome：	24 weeks	Measure method：

指标中文名：	ELISA检测受试者基线及完全缓解时血清IL-4、IL-7、IL-9、IL-15、IL-21水平	指标类型：	次要指标
Outcome：	The levels of serum IL-4,IL-7,IL-9,IL-15 and IL-21 in the participants were measured using the ELISA method at baseline and during complete remission.	Type：	Secondary indicator
测量时间点：	24周	测量方法：
Measure time point of outcome：	24 weeks	Measure method：

指标中文名：	免疫组化检测受试者基线及完全缓解时同一皮损部位pJAK1、pJAK3、pSTAT3、pSTAT6水平	指标类型：	次要指标
Outcome：	Using immunohistochemistry methods to detect the levels of pJAK1, pJAK3, pSTAT3, and pSTAT6 at the same skin lesion site in participants at baseline and complete remission.	Type：	Secondary indicator
测量时间点：	24周	测量方法：
Measure time point of outcome：	24 weeks	Measure method：

指标中文名：	RNA-seq分析受试者基线及完全缓解时同一皮损部位转录组变化差异	指标类型：	次要指标
Outcome：	The differences in transcriptome changes at the same lesion site between baseline and complete remission were analyzed using RNA-seq method.	Type：	Secondary indicator
测量时间点：	24周	测量方法：
Measure time point of outcome：	24 weeks	Measure method：

采集人体标本：

Collecting sample(s)
from participants：

标本中文名：	血液标本	组织：
Sample Name：	Blood sample	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：	皮肤组织标本	组织：
Sample Name：	Skin sample	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）：

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	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：	病例记录表
Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：	Case Record Form
数据与安全监察委员会： Data and Safety Monitoring Committee：	有/Yes
注册人： Name of Registration：	2024-07-09 10:20:42