SH229 Tablets Combined With Daclatasvir Dihydrochloride Tablets in Treatment Adult Patients With Chronic Hepatitis C

A Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of SH229 Tablets Combined With Daclatasvir Dihydrochloride Tablets in Treatment Adult Patients With Chronic Hepatitis C

Phase II: Exploring the efficacy and safety of different doses of SH229 tablets combined with fixed-dose Daclatasvi dihydrochloride (DCV) tablets in the treatment of adult patients with chronic hepatitis C for 12 weeks, providing a basis for the design and implementation of phase III clinical trials.

Phase III: Confirmation of the efficacy and safety of SH229 tablets combined with Daclatasvi dihydrochloride (DCV) tablets in the treatment of adult patients with chronic hepatitis C for 12 weeks, providing a sufficient basis for drug registration and clinical use.

It is estimated that China has a population of over 10 million infected with HCV and also a highly variable HCV genotype geographic distribution. A simple, universal, non-genotype-specific treatment regimen is preferred for anti-HCV treatment in clinical practice and public health. The combination regimen of SH229 and DCV is expected to completely suppress HCV replication in subjects chronically infected with HCV and achieve a sustained virologic response.

Inclusion Criteria:

• Willing and able to provide written informed consent.

• Subjects should be able to follow the instructions for the study drug and be able to complete screening, on-treatment, and post treatment assessments.

• Male or female, age above 18 years

• Body mass index ( BMI ) between 18 and 32 kg/m2 at Screening.

• Confirmation of chronic HCV infection, which meets one of the following: (a) positive for anti-HCV antibodies, HCV RNA or HCV genotyping results within ≤ 6 months of screening, or (b) liver biopsy ≤ 12 months of screening.

• HCV RNA above 10^4 IU/mL at Screening by the Central Laboratory.

• HCV genotype 1, 2, 4, 5, 6, or indeterminate assessed at Screening by the Central Laboratory.

• Classification as treatment naïve or treatment experienced (approximately 20% of subjects may be treatment experienced):

  1. Treatment naïve is defined as having never been exposed to approved or experimental HCV-specific direct-acting antiviral agents ( DAA ) or prior treatment of HCV with interferon either with or without RBV.
  2. Treatment experienced is defined as prior treatment failure to a regimen containing IFN-based antiviral (INF-α, β or PEG-IFN ± ribavirin) and met one of the following: (i) Non-Responder: Subject did not achieve undetectable HCV RNA levels while ontreatment,, (ii) Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels duringtreatment but did not achieve SVR, (iii) Terminate the treatment , according to associated-HCV therapy adverse events by subject reported or medical records demonstrated.

• Cirrhosis Determination (approximately 20% of subjects may have cirrhosis)：

  1. Cirrhosis is defined as any one of the following: (i) Fibroscan with a result of >12.5 kPa within ≤ 6 months of screening, (ii) Liver biopsy showing cirrhosis within ≤ 12 months of screening.
  2. Absence of cirrhosis is defined as any one of the following:(i) Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of screening, (ii) Liver biopsy showing non-cirrhosis within ≤ 12 months of screening.

Exclusion Criteria:

• Exposure nucleotide analogue including HCV NS3-4A inhibitor, HCV NS5B inhibitor or any HCV NS5A inhibitor before baseline/Day 1.
• Receive IFN-based antiviral therapy within 6 months prior to baseline/day 1.
• Oral or injection of RBV within 3 months prior to baseline/Day 1.
• Systemic use of potent immunomodulators (eg, adrenocortical hormone, thymosin alpha, etc.) for more than 2 weeks prior to baseline/day 1, or expected to be exposed to these agents during the study.
• Use of amiodarone within 2 months before baseline/day 1.
• Positive for Hepatitis B surface antigen (HBsAg) or anti-human immunodeficiency virus antibody (HIV Ab) at screening.
• Evidence of decompensatory liver function, including but not limited to total serum bilirubin (TBIL) above twice of the upper limit of normal (ULN), serum albumin (ALB) below 35 g/L or prothrombin activity (PTA) below 60% confirmed on repeated testing, previous or present history of ascites, upper gastrointestinal bleeding and/or hepatic encephalopathy, or with a liver function reserve of Child-Pugh class B or C.
• Primary liver cancer confirmed or evidenced by serum alfa-fetoprotein (AFP) above 100 ng/ml or liver imaging study showing suspected nodules.
• liver disease of a non-HCV etiology (e.g. alcoholic liver disease, nonalcoholic steatohepatitis, drug-induced hepatitis, autoimmune hepatitis, Wilson disease or hemochromatosis, etc.).
• Subjects has the following laboratory parameters at screening: ALT or AST>10×ULN, WBC < 3×109 /L, ANC< 1.5×109 /L（or < 1.25×109 /L for cirrhotics ), PLT< 50×109 /L, Hb < 100 g/L, INR > 1.5×ULN, CLcr < 50 mL/min（calculated by the Cockcroft-Gault equation ）.
• Uncontrolled diabetes mellitus (HbA1c > 8.0% at screening).
• Uncontrolled hyperthyroidism or diminished.
• Psychiatric or neurologic disorders, including previous or family history of psychiatric disorders (especially depression, depressive state, epilepsy or hysteria).
• Serious cardiovascular disorders, including uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥100 mmHg), heart insufficiency of New York Heart Association class III or above, history of myocardial infarction within 6 months before the screening, history of percutaneous transluminal coronary angioplasty within 6 months before the screening, unstable angina pectoris, or QTc interval (Fridericia correction formula QTc = QT×RR^-1/3) at or above 450 mse, second- or third-grade atrioventricular block or any other uncontrolled arrhythmias confirmed on repeated electrocardiography on screening.
• Serious hematologic disorders (e.g. anemia, hemophilia, etc.).
• Serious kidney diseases (e.g. chronic kidney disease, kidney insufficiency, etc.).
• Serious gastrointestinal disorders, (e.g. peptic ulcer, colitis, etc.) or post operative condition that could interfere with the absorption of the study drug.
• Serious respirator disorders, (e.g. active pulmonary tuberculosis, lung infection, chronic obstructive pulmonary disease, pulmonary interstitial disease, etc.).
• Malignancy within the 5 years prior to screening, with the exception of specific cancers that have been cured by surgical resection (basal cell skin cancer, etc).
• Solid organ transplantation.
• Hypersensitive predisposition or a known history of serious allergy, especially to the investigational products and substances.
• Positive urine drug screening at screening, or Clinically-relevant alcohol or drug abuse within 12 months of screening, and compliance and effectiveness evaluated by the investigator.
• Positive screening serum pregnancy test or baseline/day 1 serum or urine pregnancy test, and women are confirmed in pregnancy or lactation.
• Women of childbearing age (menopausal women aged ≤ 50 years old are also considered to have fertility), or partners who are women of childbearing age cannot comply with voluntary effective contraceptive measures during the 6 months from screening to the last dose of test drug.
• Use of any prohibited concomitant medications as described in protocol.
• Participated in clinical studies or previously participated within 3 months prior to baseline/Day 1.
• Conditions which investigator judges that it is not suitable for enrollment.