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

A Phase 3, Randomized, Multicenter, Double-blind, Double-dummy, Parallel-controlled Study to Evaluate the Safety and Efficacy of HS-10234 25 mg QD Versus TDF 300 mg QD for the Treatment of Patients With HBeAg+/- Chronic HBV Infection.

The primary objective of this study is to compare the safety and efficacy of HS-10234 versus tenofovir disoproxil fumarate (TDF) in treatment-naive and treatment-experienced adults with chronic hepatitis B virus (HBV) 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:

  1. Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study screening.
  2. 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.
  3. Documented evidence of chronic HBV infection (e.g. HBsAg positive for more than 6 months).
  4. 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.
  5. 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.
  6. Any previous treatment with interferon (pegylated or non-pegylated) must have ended at least 6 months prior to the baseline visit.
  7. 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).

  9) 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:

  1. Pregnant women, women who are breastfeeding or who believe they may wish to become pregnant during the course of the study.

  2. Males and females of reproductive potential who are unwilling to use an "effective", protocol specified method(s) of contraception during the study.

  3. Co-infection with HCV virus, HIV, or HDV.

  4. Evidence of hepatocellular carcinoma (e.g. as evidenced by recent imaging).

  5. Any history of, or current evidence of, clinical hepatic decompensation (e.g. ascites encephalopathy or variceal hemorrhage).

  6. 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)

  7. Received solid organ or bone marrow transplant.

  8. Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the investigator.

  9. Significant bone disease (e.g. osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, osteochrondroses), or multiple bone fractures.

  10. 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).

  11. Currently receiving therapy with immunomodulators (e.g. corticosteroids), investigational agents, nephrotoxic agents, or agents capable of modifying renal excretion.

  12. Known hypersensitivity to study drugs, metabolites, or formulation excipients.

  13. Current alcohol or substance abuse judged by the investigator to potentially interfere with participant compliance.

  14. 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.

  15. Subjects on prohibited concomitant medications. Subjects on prohibited medications, otherwise eligible, will need a wash out period of at least 30 days.