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A Novel Combination Therapeutic Strategy Aiming to Functional Cure for Chronic Hepatitis B Virus Infection (A)

Hepatitis B virus (HBV) infection is a major public health threat in China. At present, a functional cure, also known as clinical cure or sustained Hepatitis B surface antigen (HBsAg) loss, is recommended as the ideal endpoint of HBV treatment. However, HBsAg loss can be achieved in less than 10% of chronic hepatitis B (CHB) patients treated with current available antiviral drug interferonα (IFNα) or nucleos(t)ide analogues (NAs) monotherapy. With the support of the national major special funding for infectious diseases from "11th Five-Year Plan" to "13th Five-Year Plan", we have implemented a pioneer clinical study of sequential combination of IFNα therapy on NAs to treat NAs-treated CHB patients (ie. New Switch Study). This is the world's first clinical trial aiming to functional cure, which increased the rate of HBsAg loss to 15% in the overall population in our study, and to 30-50% among those with lower baseline HBsAg levels. How to further improve the HBsAg loss rate is an urgent issue for us. The key point of achieving functional cure is to reverse the HBV-specific T cell exhaustion and establish the long-term immune control against HBV infection. Programmed death-1(PD-1)/programmed death-ligand 1 (PD-L1) axis blockade has been demonstrated to reinvigorate exhausted CD8+ T cells, and would be a potential strategy to treat chronic HBV infection. In this study, a large multicenter prospective study will be performed to explore the safety and efficacy of a novel combination strategy involving immune checkpoint inhibitor (anti-PD-1/anti-PD-L1 antibody) and IFNα in CHB patients, observe the HBsAg loss rate in NA-treated CHB patients receiving this combination strategy, evaluate the potential of breaking immune tolerance by this strategy, and further assess its efficacy to further improve the clinical cure rate on the basis of New Switch Study. Based on New Switch Study, this study further attempts to reverse T cell exhaustion in CHB patients, explore a novel platform of combination therapy development for clinical cure, and ultimately increase the HBsAg loss rate to higher than 50% in overall patients. The implementation of the project is expected to reduce the burden of HBV infection in China and contribute to the goal of global elimination of hepatitis B and C by 2030 (WHO 2030).

研究概览

地位

招聘中

条件

干预/治疗

研究类型

介入性

注册 (估计的)

1200

阶段

  • 阶段2

联系人和位置

本节提供了进行研究的人员的详细联系信息,以及有关进行该研究的地点的信息。

学习联系方式

研究联系人备份

学习地点

    • Chongqing Municipality
      • Chongqing、Chongqing Municipality、中国、400010
        • 招聘中
        • The 2nd affiliated Hospital of Chongqing Medical University
        • 首席研究员:
          • HONG REN, Professor
        • 接触:
        • 接触:

参与标准

研究人员寻找符合特定描述的人,称为资格标准。这些标准的一些例子是一个人的一般健康状况或先前的治疗。

资格标准

适合学习的年龄

18年 至 60年 (成人)

接受健康志愿者

不

有资格学习的性别

全部

描述

Inclusion Criteria:

  1. Sign the informed consent form before inclusion and be able to complete the study according to the study requirements;
  2. 18-60 years old.
  3. NAs-naive/NAs-experienced CHB patients.

Exclusion Criteria:

  1. A history of allergy, or who are suspected by the researcher to be allergic to the active ingredient of the drug under study or its excipients;
  2. Use of inhibitors, inducers or substrates of CYP3A4 within 28 days before enrollment;
  3. Systematical use of immunosuppressants, immunomodulators (thymosin) and cytotoxic drugs within 6 months before enrollment, or vaccination of live attenuated vaccine within 1 month before enrollment;
  4. Acute infection within 2 weeks before enrollment which requires intravenous antibiotic treatment, or existing infection which requires anti-infection treatment when enrollment;
  5. Clinically significant acute and chronic liver disease not caused by HBV infection (judged by reseachers);
  6. Confirmed or suspected decompensated cirrhosis, including but not limited to: hepatic encephalopathy, hepatorenal syndrome, bleeding from esophageal varices, splenomegaly, ascites, etc, or evidence of progressive liver fibrosis;
  7. Primary liver cancer, or alpha-fetoprotein (AFP) is greater than 50 ug/L or imaging suggests the possibility of malignant liver lesions, or other malignant tumors or a history of other malignant tumors within 5 years before enrollment (except that the malignant tumors have been completely relieved after treatment and patients have not received additional medical or surgical intervention within 3 years before screening);
  8. A history of pathological fracture or osteoporosis;
  9. Gastrointestinal dysfunction or gastrointestinal diseases that might affect the absorption of oral drugs, such as severe gastric ulcer, erosive gastritis, partial gastrectomy, and persistent gastrointestinal symptoms (such as nausea, vomiting, or diarrhea) >2 grades;
  10. Serious diseases of circulatory, respiratory, urinary, blood, metabolic, immune, mental, neurological, renal and other systems;
  11. Major trauma or major surgery within 3 months before enrollment, or planned surgery during the study period;
  12. Blood donation/loss ≥ 400 mL within 3 months before enrollment, or given a blood transfusion within 3 months before enrollment, or blood donation/loss ≥ 200 mL within 1 month before enrollment;
  13. Platelet count<90 × 10^9/L, white blood cell count<3.0 × 10^9/L, neutrophil count<1.3 × 10^9/L, total serum bilirubin>2 × upper limit of normal (ULN), albumin<30 g/L, creatinine clearance ≤ 60 mL/min (calculated by CKD-EPI formula), or international normalized ratio of prothrombin time (INR)>1.5 (unless receiving stable anticoagulant therapy);
  14. Hepatitis C virus (HCV) antibody (+), HIV antigen/antibody (+), or treponema pallidum antibody (+) and rapid plasma regain (RPR) test (+);
  15. A history of continuous alcohol abuse within 3 years before enrollment (average daily alcohol consumption exceeds 20 gram);
  16. A history of drug dependence or drug abuse within 1 year before enrollment;
  17. Those who have participated in clinical trials of other investigational drugs or medical devices and taken investigational drugs or used medical devices within 3 months before enrollment;
  18. Female in suckling period or pregnancy test (+) during screening;
  19. Subjects who are considered by the researcher to have other factors that are not suitable for the study

学习计划

本节提供研究计划的详细信息,包括研究的设计方式和研究的衡量标准。

研究是如何设计的?

设计细节

  • 主要用途:治疗
  • 分配:非随机化
  • 介入模型:并行分配
  • 屏蔽:无(打开标签)

武器和干预

参与者组/臂
干预/治疗
实验性的:NAs combined with Sintilimab/Envafolimab

NAs (Once/day, 1 capsule/time, oral)combined with Sintilimab(anti-PD-1 antibody, once/three weeks, dose lower than the dose used in cancer patients, intravenous injection) /Envafolimab(anti-PD-L1 antibody, once/two weeks, dose lower than the dose used in cancer patients, subcutaneous injection), followed by NAs monotherapy

Sintilimab(anti-PD-1 antibody),once/three weeks, dose lower than the dose used in cancer patients, intravenous injection; Envafolimab(anti-PD-L1 antibody),once/two weeks, dose lower than the dose used in cancer patients, subcutaneous injection

其他名称:
  • Sintilimab(anti-PD-1 antibody)
  • Envafolimab(anti-PD-L1 antibody)

NAs(ETV/TDF/TAF), Once/day, 1 capsule/time, oral

有源比较器:NAs

NAs(Once/day, 1 capsule/time, oral)

NAs(ETV/TDF/TAF), Once/day, 1 capsule/time, oral

研究衡量的是什么?

主要结果指标

结果测量
措施说明
大体时间
Serum HBsAg
大体时间:Baseline

Serum HBsAg level

Baseline
Serum HBsAg
大体时间:24 weeks after the treatment

Serum HBsAg level

24 weeks after the treatment
Serum HBsAg
大体时间:48 weeks after the treatment

Serum HBsAg level

48 weeks after the treatment
Serum HBsAg
大体时间:24 weeks after the end of treatment

Serum HBsAg level

24 weeks after the end of treatment
Serum HBV DNA
大体时间:Baseline

Serum HBV DNA level

Baseline
Serum HBV DNA
大体时间:24 weeks after the treatment

Serum HBV DNA level

24 weeks after the treatment
Serum HBV DNA
大体时间:48 weeks after the treatment

Serum HBV DNA level

48 weeks after the treatment
Serum HBV DNA
大体时间:24 weeks after the end of treatment

Serum HBV DNA level

24 weeks after the end of treatment
Serum alanine aminotransferase (ALT)
大体时间:Baseline

Serum ALT level

Baseline
Serum alanine aminotransferase (ALT)
大体时间:24 weeks after the treatment

Serum ALT level

24 weeks after the treatment
Serum alanine aminotransferase (ALT)
大体时间:48 weeks after the treatment

Serum ALT level

48 weeks after the treatment
Serum alanine aminotransferase (ALT)
大体时间:24 weeks after the end of treatment

Serum ALT level

24 weeks after the end of treatment

其他结果措施

结果测量
措施说明
大体时间
Other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)
大体时间:Baseline

Levels of other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)

Baseline
Other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)
大体时间:24 weeks after the treatment

Levels of other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)

24 weeks after the treatment
Other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)
大体时间:48 weeks after the treatment

Levels of other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)

48 weeks after the treatment
Other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)
大体时间:24 weeks after the end of treatment

Levels of other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)

24 weeks after the end of treatment
Immune response of T and B cells
大体时间:Baseline

Frequencies and functions of T and B cells (tested by flowcytometry/FluoroSpot/ELISPOT)

Baseline
Immune response of T and B cells
大体时间:24 weeks after the treatment

Frequencies and functions of T and B cells (tested by flowcytometry/FluoroSpot/ELISPOT)

24 weeks after the treatment
Immune response of T and B cells
大体时间:48 weeks after the treatment

Frequencies and functions of T and B cells (tested by flowcytometry/FluoroSpot/ELISPOT)

48 weeks after the treatment
Immune response of T and B cells
大体时间:24 weeks after the end of treatment

Frequencies and functions of T and B cells (tested by flowcytometry/FluoroSpot/ELISPOT)

24 weeks after the end of treatment
Virus and host genome
大体时间:Baseline

Detect virus and host genome using peripheral blood and liver tissue by sequencing

Baseline
Virus and host genome
大体时间:24 weeks after the treatment

Detect virus and host genome using peripheral blood and liver tissue by sequencing

24 weeks after the treatment
Virus and host genome
大体时间:48 weeks after the treatment

Detect virus and host genome using peripheral blood and liver tissue by sequencing

48 weeks after the treatment
Virus and host genome
大体时间:24 weeks after the end of treatment

Detect virus and host genome using peripheral blood and liver tissue by sequencing

24 weeks after the end of treatment

合作者和调查者

在这里您可以找到参与这项研究的人员和组织。

赞助

合作者

调查人员

  • 研究主任:Hong Ren, MM、The Second Affiliated Hospital of Chongqing Medical University

研究记录日期

这些日期跟踪向 ClinicalTrials.gov 提交研究记录和摘要结果的进度。研究记录和报告的结果由国家医学图书馆 (NLM) 审查,以确保它们在发布到公共网站之前符合特定的质量控制标准。

研究主要日期

学习开始 (实际的)

2023年10月10日

初级完成 (估计的)

2026年12月31日

研究完成 (估计的)

2026年12月31日

研究注册日期

首次提交

2026年9月21日

首先提交符合 QC 标准的

2026年9月29日

首次发布 (实际的)

2026年10月1日

研究记录更新

最后更新发布 (实际的)

2026年10月1日

上次提交的符合 QC 标准的更新

2026年9月29日

最后验证

2026年9月1日

更多信息

与本研究相关的术语

其他研究编号

  • 2025-0215

计划个人参与者数据 (IPD)

计划共享个人参与者数据 (IPD)?

不

药物和器械信息、研究文件

研究美国 FDA 监管的药品

不

研究美国 FDA 监管的设备产品

不

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