Chronic Hepatitis B
Conditions
Brief summary
To evaluate the efficacy and safety of combined/uncombined nucleoside (acid) analogues of TQA3810 tablets.
Interventions
DRUGTQA3810 tablets+NUC
TQA3810 is a novel, effective and highly selective small-molecule oral Toll-like receptors-8 agonist.
DRUGPlacebo+NUC
NUC: Entecavir Dispersible Tablets, Inhibit viral replication; Tenofovir Disoproxil Fumarate Tablets, Nucleotide reverse transcriptase inhibitors; Tenofovir Alafenamide Fumarate Tablets, Inhibit HBV replication.
Sponsors
Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-70 (including boundary values), male or female. * Serum virological criteria: serum HBsAg positive for more than 6 months or evidence of chronic hepatitis B for more than 6 months. During the screening period, 100 IU/ml≤HBsAg quantification ≤10000 IU/ml. * No obvious cirrhosis was found by the researchers. * The subjects can communicate well with the researchers, understand and comply with the requirements of this study, and understand and sign the informed consent. * The 12-lead electrocardiogram was normal, or there were no clinically significant abnormal values as assessed by the investigator. Treated patients must meet the following conditions: * Subjects must have received oral nucleoside (acid) therapy (entecavir/ Tenofovir alafenamide Fumarate tablets/Tenofovir Disoproxil Fumarate Tablets) for ≥6 months prior to screening and stable treatment regimen for ≥3 months prior to screening. * Patients with medical history 6 months or more before enrollment had HBV DNA\< the lower limit of normal detection, and hepatitis B virus (HBV) DNA\<20 IU/mL was detected by Roche COBAS Taqman during the screening period. Newly treated patients need to meet the following conditions: * At the time of screening, subjects had never received antiviral treatment for chronic hepatitis B (oral nucleoside drugs and interferon), or had received irregular antiviral treatment in the past, and had not received any antiviral treatment for chronic hepatitis B in the first 3 months of enrollment. * HBV DNA≥2000 IU/mL(Roche COBAS Taqman).
Exclusion criteria
* Combined with other viral infections such as hepatitis A virus，hepatitis C virus, hepatitis D virus, hepatitis E virus, human immunodeficiency virus，syphilis (syphilis antibody positive by the researchers to determine the need for treatment). If hepatitis C virus (HCV) antibody positive, HCV RNA negative can not be excluded. * Patients with significant fibrosis or cirrhosis before or at the time of screening: liver histopathological findings indicating Metavir F3 or F4 within 1 year before screening; FibroScan≥ 9.7 kPa 6 months before screening in treated patients and ≥ 12.4 kPa 6 months before screening in newly treated patients; Abdominal ultrasonography suggested suspected cirrhosis. Previous history of hepatic decompensation or screening period of hepatic decompensation, such as ascites, hepatic encephalopathy, esophageal and gastric varices bleeding, etc. * Patients with a history of hepatocellular carcinoma (HCC) before or at the time of screening, or who may be at risk for HCC, such as suspicious nodules on imaging, or abnormal AFP (AFP\>50ng/mL), should be excluded from HCC before enlisting. * A history of malignant tumors within 5 years prior to screening, except for certain cancers that can be completely cured by surgical resection (such as skin basal cell carcinoma). Subjects being evaluated for active or suspected malignancy at the time of screening. * Patients with other chronic liver diseases, including but not limited to autoimmune liver disease, alcoholic liver disease, hepatolenticular degeneration, etc. * Have previously received organ transplantation and bone marrow transplantation. * Patients with uncontrolled thyroid disease. * Eye diseases: including fundus lesions (cotton wool changes in the fundus with symptoms) and retinopathy. * Autoimmune diseases include but are not limited to: systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, sarcoidosis, psoriasis, autoimmune uveitis, etc. * Current alcohol and drug abuse was determined by the investigator. Subjects with a history of excessive alcohol use. A history of excessive alcohol use was defined as alcohol consumption \>210g per week for men and \>140g for women in the past 12 months. Alcohol intake (g) = amount of alcohol consumed (ml) × alcohol degree % × 0.8. * Blood transfusion ≤2 months before screening and/or blood donation ≤1 month before screening. Note: Subjects were not allowed to donate blood throughout the study period. * Have a history of allergy to the experimental drug or its excipients; * Female subjects are pregnant, breastfeeding or have positive pregnancy results during the screening period or during the test; * Those that researchers believe should not be included.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) during the study period | Up to 52 months | The study required collection of any adverse medical events, whether causally associated with the investigational drug or not, from the time the subject signed the informed consent to 28 days after the end of study medication or the initiation of other anti-HBV therapy (whichever came first). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HBV DNA level changes and drug resistance monitoring | 24 weeks | Changes in HBV DNA levels from baseline and drug resistance monitoring. |
| HBeAg level change | 24 weeks | Changes in HBeAg levels from baseline. |
| HBsAg clearance and/or serological conversion | 24 weeks | Percentage of subjects with HBsAg clearance and/or serological conversion. |
| HBeAg clearance and/or serological conversion | 24 weeks | Percentage of subjects with HBeAg clearance and/or serological conversion |
| HBsAg level decreased by ≥0.5log10 IU/ml | 24 weeks | Proportion of subjects with HBsAg levels decreased at least 0.5log10 IU/ml |
| Changes of HBV RNA and hepatitis B core-related antigen (HBcrAg) levels during treatment | 24 weeks | Changes of HBV RNA and HBcrAg levels from baseline during treatment |
| Peak time (Tmax) | In 60 minutes pre-dose on day 1, 0.5, 1, 2, 4, 12 hours after dose; Day 15 within 60 minutes pre-dose; Day 29 within 60 minutes pre-dose; Day 57 within 60 minutes pre-dose; Day 85 within 60 minutes pre-dose, 0.5, 1, 2, 4, 12 hours after dose | Time to peak blood concentration after a single dose. |
| Peak Concentration | In 60 minutes pre-dose on day 1, 0.5, 1, 2, 4, 12 hours after dose; Day 15 within 60 minutes pre-dose; Day 29 within 60 minutes pre-dose; Day 57 within 60 minutes pre-dose; Day 85 within 60 minutes pre-dose, 0.5, 1, 2, 4, 12 hours after dose | The highest plasma drug concentration that can be achieved after medication. |
| Area under blood concentration-time curve (AUC) | In 60 minutes pre-dose on day 1, 0.5, 1, 2, 4, 12 hours after dose; Day 15 within 60 minutes pre-dose; Day 29 within 60 minutes pre-dose; Day 57 within 60 minutes pre-dose; Day 85 within 60 minutes pre-dose, 0.5, 1, 2, 4, 12 hours after dose | The amount of drug absorbed into the human circulation after a single dose can be estimated using the area under the blood concentration-time curve. |
| Changes in serum HBsAg | 24 weeks | Changes in serum HBsAg from baseline at 24 weeks |
| Plasma clearance | In 60 minutes pre-dose on day 1, 0.5, 1, 2, 4, 12 hours after dose; Day 15 within 60 minutes pre-dose; Day 29 within 60 minutes pre-dose; Day 57 within 60 minutes pre-dose; Day 85 within 60 minutes pre-dose, 0.5, 1, 2, 4, 12 hours after dose | How many milliliters of plasma can the kidneys completely clear in unit time (per minute). |
| Elimination half-life time | In 60 minutes pre-dose on day 1, 0.5, 1, 2, 4, 12 hours after dose; Day 15 within 60 minutes pre-dose; Day 29 within 60 minutes pre-dose; Day 57 within 60 minutes pre-dose; Day 85 within 60 minutes pre-dose, 0.5, 1, 2, 4, 12 hours after dose | The time it takes for the plasma concentration to drop by half |
| Peaking Time | In 60 minutes pre-dose on day 1, 0.5, 1, 2, 4, 12 hours after dose; Day 15 within 60 minutes pre-dose; Day 29 within 60 minutes pre-dose; Day 57 within 60 minutes pre-dose; Day 85 within 60 minutes pre-dose, 0.5, 1, 2, 4, 12 hours after dose | The time required to reach peak steady-state concentration after administration. |
| Steady state maximum concentration | In 60 minutes pre-dose on day 1, 0.5, 1, 2, 4, 12 hours after dose; Day 15 within 60 minutes pre-dose; Day 29 within 60 minutes pre-dose; Day 57 within 60 minutes pre-dose; Day 85 within 60 minutes pre-dose, 0.5, 1, 2, 4, 12 hours after dose | The highest blood concentration that occurs After stabilization |
| Steady state minimal concentration | In 60 minutes pre-dose on day 1, 0.5, 1, 2, 4, 12 hours after dose; Day 15 within 60 minutes pre-dose; Day 29 within 60 minutes pre-dose; Day 57 within 60 minutes pre-dose; Day 85 within 60 minutes pre-dose, 0.5, 1, 2, 4, 12 hours after dose | The lowest blood concentration that occurs after stabilization. |
| Area under steady-state blood concentration-time curve | In 60 minutes pre-dose on day 1, 0.5, 1, 2, 4, 12 hours after dose; Day 15 within 60 minutes pre-dose; Day 29 within 60 minutes pre-dose; Day 57 within 60 minutes pre-dose; Day 85 within 60 minutes pre-dose, 0.5, 1, 2, 4, 12 hours after dose | The area under the curve obtained with blood drug concentration as the vertical axis and time as the horizontal axis after administration. |
| Evaluate whether TQA3810 will affect the heart rate-corrected QT interval (QTc) of newly treated/treated chronic hepatitis B patients | 24 weeks | Evaluate whether TQA3810 will affect the QTc interval of newly treated/treated chronic hepatitis B patients |
| Pharmacodynamic characteristics (IFN-γ, IL-1RA, CCL2, CCL4, CCL8, CCL11, CCL20, CXCL8, IL-12p70, IL-12p40, TNF-α, CRP) | In 60 minutes pre-dose on day 1, 0.5, 1, 2, 4, 12 hours after dose; Day 15 within 60 minutes pre-dose; Day 29 within 60 minutes pre-dose; Day 57 within 60 minutes pre-dose; Day 85 within 60 minutes pre-dose, 0.5, 1, 2, 4, 12 hours after dose | Characteristics of IFN-γ, interleukin-1 receptor antagonist (IL-1RA), chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligands 4 (CCL4) , Chemokine (C-C motif) ligands 8 (CCL8), Chemokine (C-C motif) ligands 11 (CCL11), Chemokine (C-C motif) ligands 20 (CCL20), C-X-C motif chemokine ligand 8 (CXCL8), IL-12p70, IL-12p40, Tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) |
| Apparent volume of distribution (Vd/F) | In 60 minutes pre-dose on day 1, 0.5, 1, 2, 4, 12 hours after dose; Day 15 within 60 minutes pre-dose; Day 29 within 60 minutes pre-dose; Day 57 within 60 minutes pre-dose; Day 85 within 60 minutes pre-dose, 0.5, 1, 2, 4, 12 hours after dose | When a drug reaches homeostasis in the body, the ratio of the amount of drug in the body to the blood concentration is called the apparent volume of distribution. |
Countries
China
Contacts
Primary ContactYanyan Yu, Doctor
Backup ContactJun Li, Doctor
Outcome results
None listed