Efficacy and Safety of SOF/VEL + RBV and SOF/VEL/VOX for 12 Weeks in HCV Subjects With GT3b and Compensated Cirrhosis

Study Overview
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Brief Summary
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Direct-acting antiviral agents (DAAs) targeting HCV have revolutionized the treatment of HCV. The efficacy of DAA-based therapy can depend on patient-related factors such as treatment experience, cirrhosis, but also on viral genotype. The high prevalence of genotype 3, which is considered difficult to cure, remains a challenge because many oral DAAs are less effective for this genotype, particularly subtype 3b than for others. Current guidance generally recommends sofosbuvir (SOF)/velpatasvir (VEL) ± ribavirin (RBV), glecaprevir/pibrentasvir and SOF/VEL/voxilaprevir (VOX) as first-line therapy for genotype 3, and an interferon-based regimen - SOF plus pegylated interferon and ribavirin is still recommended as an alternative treatment option. These recommendations are based on clinical data generated in regions where genotype 3a predominates. Our recent study indicated that sofosbuvir plus ribavirin for 24 weeks in subjects with HCV genotype 3 infection resulted in high rates of SVR. However, the SVR12 rate among subjects with genotype 3b was lower than that observed in subjects with genotype 3a infection, particularly among treatment-experienced subjects with cirrhosis. Our study aimed to investigate the efficacy and safety of SOF/VEL plus RBV for 12 weeks or SOF/VEL/VOX for 12 weeks in DAAs treatment naïve HCV subjects with GT3b, compensated cirrhosis in China.

Detailed Description
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Chronic hepatitis C virus (HCV) infection, which may lead to cirrhosis and hepatocellular carcinoma, is a major cause of chronic liver disease worldwide. Genotype 3 is the second most common genotype globally, accounting for approximately 18% of all adult HCV infections. Subjects with HCV genotype 3 infection, particularly genotype 3b, have a greater risk of developing hepatic steatosis, more rapid progression of hepatic fibrosis and cirrhosis, and hepatocellular carcinoma. Although there is only a small percentage of HCV subjects with genotype 3 in East Asia (5.4%) and China (8.7%), genotype 3b represents more than 50% of genotype 3 subjects in China,compared to most other regions of the world where genotype 3a predominates. In certain provinces of China, such as Yunnan Guizhou, and Chongqing, genotype 3b is the predominant HCV subtype among genotype 3 subjects. Direct-acting antiviral agents (DAAs) targeting HCV have revolutionized the treatment of HCV. The efficacy of DAA-based therapy can depend on patient-related factors such as treatment experience, cirrhosis, but also on viral genotype. The high prevalence of genotype 3, which is considered difficult to cure, remains a challenge because many oral DAAs are less effective for this genotype, particularly subtype 3b than for others. Current guidance generally recommends sofosbuvir (SOF)/velpatasvir (VEL) ± ribavirin (RBV), glecaprevir/pibrentasvir and SOF/VEL/voxilaprevir (VOX) as first-line therapy for genotype 3, and an interferon-based regimen - SOF plus pegylated interferon and ribavirin is still recommended as an alternative treatment option. These recommendations are based on clinical data generated in regions where genotype 3a predominates. Our recent study indicated that sofosbuvir plus ribavirin for 24 weeks in subjects with HCV genotype 3 infection resulted in high rates of SVR. However, the SVR12 rate among subjects with genotype 3b was lower than that observed in subjects with genotype 3a infection, particularly among treatment-experienced subjects with cirrhosis. Our study aimed to investigate the efficacy and safety of SOF/VEL plus RBV for 12 weeks or SOF/VEL/VOX for 12 weeks in DAAs treatment naïve HCV subjects with GT3b, compensated cirrhosis in China.

Official Title
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Efficacy and Safety of Sofosbuvir/Velpatasvir Plus Ribavirin for 12 Weeks or Sofosbuvir/Velpatasvir/Voxilaprevir for 12 Weeks in DAA Treatment Naïve HCV Subjects With GT3b, Compensated Cirrhosis in China

Conditions
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Hepatitis C, Cirrhosis

Intervention / Treatment
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* Drug: Sofosbuvir/Velpatasvir + Ribavirin
* Drug: Sofosbuvir/Velpatasvir/Voxilaprevir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent Male or female, age ≥18 years Body mass index (BMI) between 18.0-35.0kg/m2 and bodyweight ≥ 40 kg Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy Anti-HCV positive at screening HCV RNA 104 IU/mL at screening by the Central Laboratory HCV genotype 3b assessed at screening by the Central Laboratory DAA treatment naïve defined as having never been exposed to approved or experimental HCV-specific direct-acting antiviral agents. Pegylated interferon/interferon based prior treatment is allowed. Cirrhosis Determination: cirrhosis is defined as any one of the following: Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥5) in 24 months before screening, or Fibroscan® with a result of >12.5 kPa in 6 months before screening The lab test at screening should meet all the criterion below: a) ALT ≤ 10 the upper limit of normal (ULN); b) AST ≤ 10 ULN; c) Total bilirubin ≤ 2 ULN; d) Platelets ≥ 60,000/L; e) Neutrophile ≥ 1,500/L; f) HbA1c ≤ 8.5%; g) Creatinine clearance (CLcr) ≥ 60 mL /min as calculated by the Cockcroft-Gault equation; h) Hemoglobin ≥ 11 g/dL for female subjects; ≥ 12 g/dL for male subjects; i) Albumin ≥ 3 g/dL; j) INR ≤ 1.7 x ULN; k) AFP <100ng/mL；if 20ng/mL≤AFP≤100ng/mL，HCC should be exclude by liver ultrasound Females of childbearing potential must have a negative serum pregnancy test at screening Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception Male subjects must agree to avoid donating sperm in 6 months after the last dose of drug Subject must be of generally good health, with the exception of chronic HCV infection, as determined by the Investigator Subject must be able to comply with the dosing instructions for study drug administration and able to complete the study schedule of assessments Exclusion Criteria: Decompensated cirrhosis, including but not limited to: prior or current ascites, variceal hemorrhage and/or hepatic encephalopathy; prior or current Child-Pugh B or C HBsAg posititve at screening Anti-HIV positive at screening Alcohol abuse Contraindication of ribavirin, including but not limited to hemoglobinapathy Pregnant or nursing female or male with pregnant female partner Use of any prohibited concomitant medications as described in Section before screening Known hypersensitivity to SOF, VEL, RBV or formulation excipients Subjects who has any of the following history: a) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson's disease, alfa-1 antitrypsin deficiency, cholangitis); b) Solid organ transplantation; c) Significant pulmonary disease, significant cardiac disease or porphyria; d) Pancreatitis; e) Autoimmune diseases (e.g., systemic lupus erythematosus, sarcoidosis, psoriasis); f) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of their psychiatric illness within the last 5 years; g) 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). Subjects under evaluation for possible malignancy are not eligible; h) Significant drug allergy (such as anaphylaxis or hepatotoxicity). Assessed as ineligible by investigators

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Sofosbuvir 400mg/velpatasvir 100mg + ribavirin 1000mg/1200mg for 12 weeks | Drug: Sofosbuvir/Velpatasvir + Ribavirin<br>* Sofosbuvir 400mg/velpatasvir 100mg + ribavirin 1000mg/1200mg for 12 weeks<br>* Other names: Epclusa;|
| Experimental: Arm 2<br>Sofosbuvir 400mg/velpatasvir 100mg/voxilaprevir 100mg for 12 weeks | Drug: Sofosbuvir/Velpatasvir/Voxilaprevir<br>* Sofosbuvir 400mg/velpatasvir 100mg/voxilaprevir 100mg for 12 weeks<br>* Other names: Vosevi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of participants with SVR12 | To evaluate the efficacy of treatment with SOF/VEL plus RBV for 12 weeks or SOF/VEL/VOX for 12 weeks in DAA treatment naïve HCV participants with GT3b, participants initiated on treatment will be assessed for viral load response at 12 weeks post treatment (SVR12). We use the proportion of participants with SVR12 as primary outcome measure. | 12 weeks post treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Number of Participants With treatment-related adverse events as assessed by CTCAE v4.0- SOF/VEL plus RBV vs. SOF/VEL/VOX. | Treatment start date through treatment completion (up to 24 weeks). |