Study of the Efficacy and Safety of HS-10234 in Patients With Chronic Hepatitis B Virus Infection

This is a phase 3, randomized, multicenter, double-blind, double-dummy, parallel-controlled, non-inferiority trial to evaluate the safety and efficacy of HS-10234 25 mg qd versus TDF 300 mg qd. Patients with chronic HBV infection who are positive or negative for the hepatitis B e antigen (HBeAg) will be randomly assigned (2:1) to receive either 25 mg HS-10234 or 300 mg TDF with matching placebo. Randomization will be done by a computer-generated allocation sequence stratified by plasma HBV DNA concentration (HBV DNA< 8 log10IU/mL；HBV DNA ≥8 log10IU/mL) and previous treatment experience (treatment-naive and treatment-experienced). All patients will receive 144 weeks of antiviral therapy. After 96 weeks of double-blind treatment, all subjects will be eligible to receive open-label HS-10234 until 144 weeks.

The primary efficacy endpoint is the proportion of patients with HBV DNA less than 20 IU/mL at week 48 in all patients who are randomly assigned and received at least one dose of study drug using a missing-equals-failed approach. Key pre-specified safety endpoints are bone and renal parameters at week 48. Other pre-specified endpoints include viral suppression, serologic response, normalization of alanine aminotransferase (ALT) levels and the emergence of resistance mutations at week 48, 96 and 144.

Inclusion criteria

• Subjects must meet all of the following inclusion criteria to be eligible for participation in this study:

• Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study screening.
• Male and non-pregnant, non-lactating females, from 18 up to 65 years of age (based on the date of the screening visit). A negative serum pregnancy test at screening is required for female subjects of childbearing potential.
• Documented evidence of chronic HBV infection (e.g. HBsAg positive for more than 6 months).
• HBeAg-positive or HBeAg-negative chronic hepatitis B with all of the following: HBV DNA ≥ 2 x 104 IU/mL; Screening serum 1 ULN < ALT level ≤ 10 ULN.
• Treatment-naive subjects (defined as < 12 weeks of oral antiviral treatment with any nucleoside or nucleotide analogue) OR treatment-experienced subjects (defined as subjects meeting all entry criteria [including HBV DNA and serum ALT criteria] and with ≥ 12 weeks of previous treatment with any nucleoside or nucleotide analogue) will be eligible for enrollment. Treatment-experienced subjects receiving oral antiviral treatment at Screening must continue their treatment regimen until the time of randomization, when it will be discontinued.
• Any previous treatment with interferon (pegylated or non-pegylated) must have ended at least 6 months prior to the baseline visit.
• Estimated creatinine clearance (CLcr) ≥ 50 mL/min（using the Cockcroft-Gault method）based on serum creatinine and actual body weight as measured at the screening evaluation, as follows:

（140-age in years）(body weight [kg]) (72)(serum creatinine [mg/dL]） 8) Normal ECG (or if abnormal, determined by the Investigator not to be clinically significant).

• Must be willing and able to comply with all study requirements.

Exclusion criteria

• Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:

• Pregnant women, women who are breastfeeding or who believe they may wish to become pregnant during the course of the study.
• Males and females of reproductive potential who are unwilling to use an "effective", protocol specified method(s) of contraception during the study.
• Co-infection with HCV virus, HIV, or HDV.
• Evidence of hepatocellular carcinoma (e.g. as evidenced by recent imaging).
• Any history of, or current evidence of, clinical hepatic decompensation (e.g. ascites encephalopathy or variceal hemorrhage).
• Abnormal hematological and biochemical parameters, including:

• Hemoglobin < 10 g/dl
• Absolute neutrophil count < 0.75 × 109/L
• Platelets ≤ 50 × 109/L
• AST or ALT > 10 × ULN
• Total Bilirubin > 2.5 × ULN
• Albumin < 3.0 g/dL
• INR > 1.5 × ULN (unless stable on anticoagulant regimen)
• Received solid organ or bone marrow transplant.
• Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the investigator.
• Significant bone disease (e.g. osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, osteochrondroses), or multiple bone fractures.
• Malignancy within the 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (basal cell skin cancer, etc).
• Currently receiving therapy with immunomodulators (e.g. corticosteroids), investigational agents, nephrotoxic agents, or agents capable of modifying renal excretion.
• Known hypersensitivity to study drugs, metabolites, or formulation excipients.
• Current alcohol or substance abuse judged by the investigator to potentially interfere with participant compliance.
• Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study or unable to comply with dosing requirements.
• Subjects on prohibited concomitant medications. Subjects on prohibited medications, otherwise eligible, will need a wash out period of at least 30 days.