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

Primary Purpose

Chronic Hepatitis b, Anti-PD-1 Antibody

Status
Not yet recruiting
Phase
Phase 4
Locations
China
Study Type
Interventional
Intervention
Anti-PD-1 antibody
NAs
Sponsored by
The Second Affiliated Hospital of Chongqing Medical University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Hepatitis b

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: 1) Sign the informed consent form before inclusion and be able to complete the study according to the study requirements; 2) From inclusion to 30 days after the last administration of the study drug, male subjects or female subjects of childbearing age are willing to voluntarily take effective contraceptive measures; 3) 18-70 years old. The weight of male subjects is not less than 45 kg, and the weight of female subjects is not less than 40 kg. Body mass index (BMI) is within the range of 18-32 kg/m^2; 4) 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

Sites / Locations

  • The 2nd affiliated Hospital of Chongqing Medical University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Group 1

Group 2

Arm Description

NAs combined with anti-PD-1 antibody, followed by NAs monotherapy

NAs

Outcomes

Primary Outcome Measures

Serum HBsAg
Serum HBsAg level
Serum HBsAg
Serum HBsAg level
Serum HBsAg
Serum HBsAg level
Serum HBsAg
Serum HBsAg level
Serum HBV DNA
Serum HBV DNA level
Serum HBV DNA
Serum HBV DNA level
Serum HBV DNA
Serum HBV DNA level
Serum HBV DNA
Serum HBV DNA level
Serum alanine aminotransferase (ALT)
Serum ALT level
Serum alanine aminotransferase (ALT)
Serum ALT level
Serum alanine aminotransferase (ALT)
Serum ALT level
Serum alanine aminotransferase (ALT)
Serum ALT level

Secondary Outcome Measures

Full Information

First Posted
February 22, 2023
Last Updated
April 25, 2023
Sponsor
The Second Affiliated Hospital of Chongqing Medical University
Collaborators
The Affiliated Hospital Of Southwest Medical University, Guizhou Provincial People's Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT05769816
Brief Title
A Novel Combination Therapeutic Strategy Aiming to Functional Cure for Chronic Hepatitis B Virus Infection (Sustained HBsAg Loss) (A)
Official Title
A Novel Combination Therapeutic Strategy Aiming to Functional Cure for Chronic Hepatitis B Virus Infection (Sustained HBsAg Loss) (A)
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
June 1, 2023 (Anticipated)
Primary Completion Date
December 31, 2025 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The Second Affiliated Hospital of Chongqing Medical University
Collaborators
The Affiliated Hospital Of Southwest Medical University, Guizhou Provincial People's Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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 interferon (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 antibody) 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Hepatitis b, Anti-PD-1 Antibody

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group 1
Arm Type
Experimental
Arm Description
NAs combined with anti-PD-1 antibody, followed by NAs monotherapy
Arm Title
Group 2
Arm Type
Active Comparator
Arm Description
NAs
Intervention Type
Drug
Intervention Name(s)
Anti-PD-1 antibody
Intervention Description
Once/two or three weeks, dose lower than the dose used in cancer patients, subcutaneous/intravenous injection
Intervention Type
Drug
Intervention Name(s)
NAs
Other Intervention Name(s)
ETV/TDF/TAF
Intervention Description
Once/day, 1 capsule/time, oral
Primary Outcome Measure Information:
Title
Serum HBsAg
Description
Serum HBsAg level
Time Frame
Baseline
Title
Serum HBsAg
Description
Serum HBsAg level
Time Frame
24 weeks after the treatment
Title
Serum HBsAg
Description
Serum HBsAg level
Time Frame
48 weeks after the treatment
Title
Serum HBsAg
Description
Serum HBsAg level
Time Frame
24 weeks after the end of treatment
Title
Serum HBV DNA
Description
Serum HBV DNA level
Time Frame
Baseline
Title
Serum HBV DNA
Description
Serum HBV DNA level
Time Frame
24 weeks after the treatment
Title
Serum HBV DNA
Description
Serum HBV DNA level
Time Frame
48 weeks after the treatment
Title
Serum HBV DNA
Description
Serum HBV DNA level
Time Frame
24 weeks after the end of treatment
Title
Serum alanine aminotransferase (ALT)
Description
Serum ALT level
Time Frame
Baseline
Title
Serum alanine aminotransferase (ALT)
Description
Serum ALT level
Time Frame
24 weeks after the treatment
Title
Serum alanine aminotransferase (ALT)
Description
Serum ALT level
Time Frame
48 weeks after the treatment
Title
Serum alanine aminotransferase (ALT)
Description
Serum ALT level
Time Frame
24 weeks after the end of treatment
Other Pre-specified Outcome Measures:
Title
Other HBV markers
Description
Levels of other HBV markers
Time Frame
Baseline
Title
Other HBV markers
Description
Levels of other HBV markers
Time Frame
24 weeks after the treatment
Title
Other HBV markers
Description
Levels of other HBV markers
Time Frame
48 weeks after the treatment
Title
Other HBV markers
Description
Levels of other HBV markers
Time Frame
24 weeks after the end of treatment
Title
Immune response of T, B, NK and myeloid cells
Description
Frequencies and functions of T, B, NK and myeloid cells (tested by flowcytometry/FluoroSpot/ELISPOT)
Time Frame
Baseline
Title
Immune response of T, B, NK and myeloid cells
Description
Frequencies and functions of T, B, NK and myeloid cells (tested by flowcytometry/FluoroSpot/ELISPOT)
Time Frame
24 weeks after the treatment
Title
Immune response of T, B, NK and myeloid cells
Description
Frequencies and functions of T, B, NK and myeloid cells (tested by flowcytometry/FluoroSpot/ELISPOT)
Time Frame
48 weeks after the treatment
Title
Immune response of T, B, NK and myeloid cells
Description
Frequencies and functions of T, B, NK and myeloid cells (tested by flowcytometry/FluoroSpot/ELISPOT)
Time Frame
24 weeks after the end of treatment
Title
Virus and host genome
Description
Detect virus and host genome (focusing on HBV genotype, resistant mutation) using peripheral blood by sequencing
Time Frame
Baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 1) Sign the informed consent form before inclusion and be able to complete the study according to the study requirements; 2) From inclusion to 30 days after the last administration of the study drug, male subjects or female subjects of childbearing age are willing to voluntarily take effective contraceptive measures; 3) 18-70 years old. The weight of male subjects is not less than 45 kg, and the weight of female subjects is not less than 40 kg. Body mass index (BMI) is within the range of 18-32 kg/m^2; 4) 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Dachuan Cai, MD
Phone
+86 18323409779
Email
cqmucdc@cqmu.edu.cn
First Name & Middle Initial & Last Name or Official Title & Degree
Min Chen, PhD
Phone
+86 17338600343
Email
mchen@hospital.cqmu.edu.cn
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hong Ren, MM
Organizational Affiliation
The Second Affiliated Hospital of Chongqing Medical University
Official's Role
Study Director
Facility Information:
Facility Name
The 2nd affiliated Hospital of Chongqing Medical University
City
Chongqing
State/Province
Chongqing
ZIP/Postal Code
400010
Country
China

12. IPD Sharing Statement

Plan to Share IPD
No

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

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