A Clinical Study of TQA3605 Tablets Monotherapy or in Combination With Nucleoside (Acid) Analogues in Treatment Naive and Treated Patients With Chronic Hepatitis B

Study Overview
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Brief Summary
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This is a randomized, double-blind Phase Ib/IIa multicenter trial. All eligible subjects will receive TQA3605 tablets or placebo in combination with nucleoside (acid) analogues. A total of 64 subjects will be enrolled.

Official Title
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Randomized, Double-blind, Placebo-controlled Phase Ib/IIa Clinical Trial to Evaluate the Efficacy and Safety of TQA3605 Tablets Monotherapy or in Combination With Nucleoside (Acid) Analogues in Treatment-naïve Patients and Treated Patients With Chronic Hepatitis B

Conditions
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Chronic Hepatitis b

Intervention / Treatment
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* Drug: Placebo
* Drug: TQA3605 tablets
* Drug: Entecavir dispersible tablets
* Drug: Tenofovir disoproxil fumarate tablet
* Drug: Tenofovir alafenamide fumarate tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects voluntarily participate in this study and sign informed consent; Male and female, ≥18 years old and ≤70 years old (subject to the date of signing the informed consent); Patients diagnosed with chronic hepatitis B (CHB) who have been serum HBsAg positive for more than 6 months and HBeAg positive or negative ; The liver fibrosis ultrasound transient imaging elastic technology (Fibroscan/FibroTouch) showed that the liver hardness (LSM) was less than 12.4 Kpa; Patients with chronic hepatitis B after treatment; Treatment-naïve patients of chronic hepatitis B patients; Exclusion Criteria: Complicated with other infected disease such as hepatitis A virus (HAV), hepatitis C virus (HCV), Hepatitis D virus (HDV), hepatitis E virus (HEV), human immunodeficiency virus (HIV), syphilis (syphilis antibody positive and need treatment determined by the investigator); Abdominal ultrasound or other imaging or histology showed suspected cirrhosis or other liver disease before or during screening; Patients have a history of hepatocellular carcinoma (HCC) before or at the time of screening, or may be at risk for HCC; Active autoimmune disease diagnosed with immunodeficiency or undergoing systemic therapy which was continuing within 2 weeks before first dosing; Currently being treated with nephrotoxic drugs or drugs that alter renal excretion; Abnormal thyroid function; Renal diseases such as chronic kidney disease and renal insufficiency or creatinine clearance (CLCr) <60 ml/min during the screening period; Hematologic and biochemical abnormalities; History of allergy to the investigational drug or its excipients; Recipients of solid organs or bone marrow transplants; A history of malignant tumors within the past 5 years; Interstitial lung disease, acute lung disease, etc.; Uncontrolled systemic diseases such as high blood pressure and diabetes; Have used any investigational drug or participated in a clinical trial within one month prior to the administration of study drug; Those who received live attenuated vaccine within 28 days before the start of study treatment, inactivated vaccine within 7 days, or planned vaccination during the study period; The investigator determines that there is any medical or psychiatric condition that puts the subject at risk, interferes with participation in the study, or interferes with the interpretation of the study results; Female subjects that were pregnant, lactating or had a positive pregnancy result during the screening period or during the trial; Male and female patients with reproductive potential who were unwilling to use effective contraceptive methods during the study period; Subjects who have any medical condition that may affect the absorption of oral drugs; Within 12 weeks prior to screening, treated chronic hepatitis B patients who had stopped taking nucleoside (acid) analogues for more than 14 consecutive days; Those considered unsuitable for enrollment by the investigators.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo +Nucleoside (acid) analogs (NAs) combination therapy 24 weeks<br>Placebo and Nucleoside (acid) analogues, taken orally once daily, continue for 24 weeks. | Drug: Placebo<br>* TQA3605 placebo tablets were orally administered under fast condition (at least 2 hours before or after meals) with warm water for a total of 24 weeks.<br>Drug: Entecavir dispersible tablets<br>* Entecavir inhibits viral replication and indicated for chronic hepatitis B treatment.<br>Drug: Tenofovir disoproxil fumarate tablet<br>* Tenofovir disoproxil fumarate is a Nucleotide reverse transcriptase inhibitor.<br>Drug: Tenofovir alafenamide fumarate tablet<br>* Tenofovir alafenamide fumarate inhibits hepatitis B virus replication.<br>|
| Active Comparator: 50 mg of TQA3605 tablets +NAs combination therapy 24 weeks<br>50 mg of TQA3605 tablets and Nucleoside (acid) analogues, taken orally once daily, continue for 24 weeks. | Drug: TQA3605 tablets<br>* TQA3605 inhibits viral replication.<br>Drug: Entecavir dispersible tablets<br>* Entecavir inhibits viral replication and indicated for chronic hepatitis B treatment.<br>Drug: Tenofovir disoproxil fumarate tablet<br>* Tenofovir disoproxil fumarate is a Nucleotide reverse transcriptase inhibitor.<br>Drug: Tenofovir alafenamide fumarate tablet<br>* Tenofovir alafenamide fumarate inhibits hepatitis B virus replication.<br>|
| Active Comparator: 100 mg of TQA3605 tablets +NAs combination therapy 24 weeks<br>100 mg of TQA3605 tablets and Nucleoside (acid) analogues, taken orally once daily, continue for 24 weeks. | Drug: TQA3605 tablets<br>* TQA3605 inhibits viral replication.<br>Drug: Entecavir dispersible tablets<br>* Entecavir inhibits viral replication and indicated for chronic hepatitis B treatment.<br>Drug: Tenofovir disoproxil fumarate tablet<br>* Tenofovir disoproxil fumarate is a Nucleotide reverse transcriptase inhibitor.<br>Drug: Tenofovir alafenamide fumarate tablet<br>* Tenofovir alafenamide fumarate inhibits hepatitis B virus replication.<br>|
| Active Comparator: 200 mg of TQA3605 tablets +NAs combination therapy 24 weeks<br>200 mg of TQA3605 tablets and Nucleoside (acid) analogues, taken orally once daily, continue for 24 weeks. | Drug: TQA3605 tablets<br>* TQA3605 inhibits viral replication.<br>Drug: Entecavir dispersible tablets<br>* Entecavir inhibits viral replication and indicated for chronic hepatitis B treatment.<br>Drug: Tenofovir disoproxil fumarate tablet<br>* Tenofovir disoproxil fumarate is a Nucleotide reverse transcriptase inhibitor.<br>Drug: Tenofovir alafenamide fumarate tablet<br>* Tenofovir alafenamide fumarate inhibits hepatitis B virus replication.<br>|
| Active Comparator: Placebo +Nucleoside (acid) analogs (NAs) combination therapy<br>Placebo taken orally once daily, continue for 12 weeks. Placebo combined with Nucleoside (acid) analogues, taken orally once daily, continue for 12 weeks. | Drug: Placebo<br>* TQA3605 placebo tablets were orally administered under fast condition (at least 2 hours before or after meals) with warm water for a total of 24 weeks.<br>Drug: Entecavir dispersible tablets<br>* Entecavir inhibits viral replication and indicated for chronic hepatitis B treatment.<br>Drug: Tenofovir disoproxil fumarate tablet<br>* Tenofovir disoproxil fumarate is a Nucleotide reverse transcriptase inhibitor.<br>Drug: Tenofovir alafenamide fumarate tablet<br>* Tenofovir alafenamide fumarate inhibits hepatitis B virus replication.<br>|
| Active Comparator: 100 mg of TQA3605 tablets +NAs combination therapy<br>100 mg of TQA3605 tablets taken orally once daily, continue for 12 weeks. 100 mg of TQA3605 tablets combined with Nucleoside (acid) analogues, taken orally once daily, continue for 12 weeks. | Drug: TQA3605 tablets<br>* TQA3605 inhibits viral replication.<br>Drug: Entecavir dispersible tablets<br>* Entecavir inhibits viral replication and indicated for chronic hepatitis B treatment.<br>Drug: Tenofovir disoproxil fumarate tablet<br>* Tenofovir disoproxil fumarate is a Nucleotide reverse transcriptase inhibitor.<br>Drug: Tenofovir alafenamide fumarate tablet<br>* Tenofovir alafenamide fumarate inhibits hepatitis B virus replication.<br>|
| Active Comparator: 200 mg of TQA3605 tablets +NAs combination therapy<br>200 mg of TQA3605 tablets taken orally once daily, continue for 12 weeks. 200 mg of TQA3605 tablets combined with Nucleoside (acid) analogues, taken orally once daily, continue for 12 weeks. | Drug: TQA3605 tablets<br>* TQA3605 inhibits viral replication.<br>Drug: Entecavir dispersible tablets<br>* Entecavir inhibits viral replication and indicated for chronic hepatitis B treatment.<br>Drug: Tenofovir disoproxil fumarate tablet<br>* Tenofovir disoproxil fumarate is a Nucleotide reverse transcriptase inhibitor.<br>Drug: Tenofovir alafenamide fumarate tablet<br>* Tenofovir alafenamide fumarate inhibits hepatitis B virus replication.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of adverse events (AEs) | The incidence of adverse events (AEs) during treatment | Up to 28 weeks | 
| Severity of adverse events (AEs) | The severity of adverse events (AEs) during treatment | Up to 28 weeks | 
| Incidence of serious adverse events (SAEs) | The incidence of serious adverse events (SAEs) during treatment | Up to 28 weeks | 
| Severity of serious adverse events (SAEs) | The severity of serious adverse events (SAEs) during treatment | Up to 28 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of abnormal laboratory test values | The incidence of abnormal laboratory values during treatment, e.g. triglycerides. | Up to 28 weeks | 
| Severity of abnormal laboratory test values | The severity of abnormal laboratory values during treatment, e.g. triglycerides. | Up to 28 weeks | 
| Deoxyribonucleic acid level of hepatitis B virus | Changes in hepatitis B virus deoxyribonucleic acid (HBV DNA) levels from baseline | At week 12 and week 24 or when subjects withdrawal from the study | 
| Hepatitis B surface antigen | Changes in serum hepatitis B surface antigen (HBsAg) from baseline | At week 12 and week 24 or when subjects withdrawal from the study | 
| Hepatitis B e antigen | Changes in serum hepatitis B e antigen (HBeAg) from baseline | At week 12 and week 24 or when subjects withdrawal from the study | 
| Serologic clearance and/or serologic conversion of HBsAg | Proportion of subjects with HBsAg serologic clearance and/or serologic conversion | At week 12 and week 24 or when subjects withdrawal from the study | 
| Serologic clearance and/or serologic conversion of HBeAg | Proportion of subjects with HBeAg serologic clearance and/or serologic conversion | At week 12 and week 24 or when subjects withdrawal from the study | 
| Virological breakthrough rate | The proportion of subjects who achieved a virological breakthrough (defined as a confirmed increase of HBV DNA levels >1.0 log10 IU/ml from the minimum during treatment). | At week 12 and week 24 or when subjects withdrawal from the study | 
| Peak time (Tmax) | Time to reach peak blood concentration after a single dose | pre-dose, 30 minutes, 1 , 2 , 4 , 6 , 12, 24 hours after administration on Day 1; pre-dose on Day 8 and Day 9; pre-dose, 30 minutes, 1, 2, 4, 6, 12, 24 hours after administration on Day 10. | 
| Peak concentration | The highest plasma drug concentration that can be achieved after medication | pre-dose, 30 minutes, 1 , 2 , 4 , 6 , 12, 24 hours after administration on Day 1; pre-dose on Day 8 and Day 9; pre-dose, 30 minutes, 1, 2, 4, 6, 12, 24 hours after administration on Day 10. | 
| Area under blood concentration-time curve (AUC) | 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 | pre-dose, 30 minutes, 1 , 2 , 4 , 6 , 12, 24 hours after administration on Day 1; pre-dose on Day 8 and Day 9; pre-dose, 30 minutes, 1, 2, 4, 6, 12, 24 hours after administration on Day 10. | 
| Apparent volume of distribution (Vd/F) | 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. | pre-dose, 30 minutes, 1 , 2 , 4 , 6 , 12, 24 hours after administration on Day 1; pre-dose on Day 8 and Day 9; pre-dose, 30 minutes, 1, 2, 4, 6, 12, 24 hours after administration on Day 10. | 
| Plasma clearance | The amount of plasma that the kidneys completely clear in unit time (per minute). | pre-dose, 30 minutes, 1 , 2 , 4 , 6 , 12, 24 hours after administration on Day 1; pre-dose on Day 8 and Day 9; pre-dose, 30 minutes, 1, 2, 4, 6, 12, 24 hours after administration on Day 10. | 
| Elimination half-life | The time it takes for the plasma concentration to drop by half. | pre-dose, 30 minutes, 1 , 2 , 4 , 6 , 12, 24 hours after administration on Day 1; pre-dose on Day 8 and Day 9; pre-dose, 30 minutes, 1, 2, 4, 6, 12, 24 hours after administration on Day 10. | 
| Steady state peak time | The time required to reach peak steady-state concentration after administration | pre-dose, 30 minutes, 1 , 2 , 4 , 6 , 12, 24 hours after administration on Day 1; pre-dose on Day 8 and Day 9; pre-dose, 30 minutes, 1, 2, 4, 6, 12, 24 hours after administration on Day 10. | 
| Steady state maximum concentration | The highest blood concentration that occurs after stabilization | pre-dose, 30 minutes, 1 , 2 , 4 , 6 , 12, 24 hours after administration on Day 1; pre-dose on Day 8 and Day 9; pre-dose, 30 minutes, 1, 2, 4, 6, 12, 24 hours after administration on Day 10. | 
| Steady state minimal concentration | The lowest blood concentration that occurs after stabilization | pre-dose, 30 minutes, 1 , 2 , 4 , 6 , 12, 24 hours after administration on Day 1; pre-dose on Day 8 and Day 9; pre-dose, 30 minutes, 1, 2, 4, 6, 12, 24 hours after administration on Day 10. |