Study to Evaluate the Safety and Efficacy of Daclatasvir/Sofosbuvir/Ribavirin for 16 Versus 24 Weeks for HCV Genotype 3 Cirrhotics
Condition: Hepatitis C; Cirrhosis
MeSH terms: Hepatitis C; Hepatitis
Intervention: daclatasvir; Sofosbuvir, Sovaldi; Ribavirin
Intervention MeSH terms: Ribavirin; Sofosbuvir
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 39.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: HCV; Genotype 3; Treatment naive; Treatment experienced

Summary:

      This is a randomized, open label, single center safety and efficacy study. At least 40
      cirrhotic subjects with HCV genotype 3 will receive standard of care treatment of sofosbuvir
      and ribavirin (SOF/RBV) as well as 60 mg daily of Daclatasvir (investigational product).
      Subjects will be randomized in a 1:1 to receive either:

        -  Group A: 16 weeks of DCV/SOF/RBV

        -  Group B: 24 weeks of DCV/SOF/RBV

      Subjects will return to the study center at various time points throughout the 16 or 24 weeks
      of treatment in addition to 12 weeks post taking last dose of study drug to monitor safety
      and efficacy. These visits will be according to standard of care.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Signed, written, informed consent must be available from the subject before any
             study-specific procedures are performed;

          2. Male or female 18-75 years of age;

          3. All of the following at least 6 months prior to screening visit:

               -  Documented HCV infection based on history of a positive serum anti-HCV antibody
                  test and/or detectable levels of HCV RNA >= 10,000 IU/mL, and

               -  Documented HCV genotype 3.

          4. Subjects with evidence of cirrhosis defined by either a liver biopsy <= 3 years from
             screening demonstrating a Metavir Fibrosis Score of F4 (or equivalent); OR Fibroscan®
             <= 1 year from screening > 12.5 kPa. If a subject is evaluated by more than one
             testing method, then the liver biopsy results take precedence;

          5. Women of childbearing potential (WOCBP) must:

               -  have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or
                  equivalent units of HCG) within 24 hours prior to the start of study drug.

               -  WOCBP must agree to follow instructions for method(s) of contraception for 7
                  months post-treatment completion.

               -  Men who are sexually active with WOCBP must agree to follow instructions for
                  method(s) of contraception for the following duration for 7 months post-treatment
                  completion.

               -  Investigators shall counsel WOCBP and male subjects who are sexually active with
                  WOCBP on the importance of pregnancy prevention and the implications of an
                  unexpected pregnancy Investigators shall advise WOCBP and male subjects who are
                  sexually active with WOCBP on the use of highly effective methods of
                  contraception. Highly effective methods of contraception have a failure rate of <
                  1% per year when used consistently and correctly.

          6. At minimum the subject agrees to the use of two methods of contraception, with at
             least one method being highly effective as listed below:

        Highly Effective Methods of Contraception

          -  Male condoms with spermicide

          -  Hormonal methods of contraception including combined oral contraceptive pills, vaginal
             ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena® by male
             subject's WOCBP partner. Female partners of male subjects participating in the study
             may use hormone-based contraceptives as one of the acceptable methods of contraception
             since they will not be receiving study drug. WOCBP cannot use hormonal contraception
             as one of the two methods of contraception because there are no data on the
             effectiveness of systemic hormonal contraceptives in women taking SOF. However, WOCBP
             can continue to use hormonal contraceptives, if necessary, in addition to 2 other
             non-hormonal methods of contraception

          -  Nonhormonal IUDs, such as ParaGard®

          -  Tubal Ligation

          -  Vasectomy

          -  Complete Abstinence - defined as complete avoidance of heterosexual intercourse and is
             an acceptable form of contraception for all study drugs. Subjects who choose complete
             abstinence are not required to use a second method of contraception, but female
             subjects must continue to have pregnancy tests. Acceptable alternate methods of highly
             effective contraception must be discussed in the event that the subject chooses to
             forego complete abstinence.

        Less Effective Methods of Contraception

          -  Diaphragm with spermicide

          -  Cervical cap with spermicide

          -  Vaginal sponge

          -  Male condom without spermicide

          -  Progestin only pills

          -  Female condom; A male and female condom must not be used together

        Azoospermic males, women who are not of childbearing potential and WOCBP who abstain from
        heterosexual activity on a continuous basis, are exempt from contraceptive requirements.
        However, WOCBP who abstain from heterosexual activity on a continuous basis must still
        undergo pregnancy testing.

        Exclusion Criteria:

          1. Subjects who lack capacity to consent for themselves;

          2. HCV Genotypes other than GT-3 infection; mixed genotype infections are not permitted;

          3. Liver histology consistent with any other co-existing cause of chronic liver disease
             (apart from fatty liver and/or Chronic Hepatitis B Virus);

          4. Body Mass Index > 40 at the Screening visit;

          5. Any of the following within one month of screening:

               -  Uncontrolled diabetes;

               -  Unstable or uncontrolled thyroid disease (subjects requiring medication to
                  control their thyroid disease are eligible if all other inclusion/exclusion
                  criteria are met).

          6. Any of the following within 6 months of screening visit, any of the following:

               -  Decompensated liver disease, esophageal variceal bleeding, or a hepatic mass
                  lesion suspicious for hepatocellular carcinoma (HCC);

               -  Subjects who have been treated for HCV infection;

               -  History of unstable or deteriorating cardiovascular or cerebrovascular disease;

               -  Alcohol and/or drug.

          7. QTcF ≥ 500 ms at the baseline visit.

          8. Any of the following laboratory abnormalities within 8 weeks of the baseline visit:

               -  Hemoglobin <8 g/dL;

               -  Absolute neutrophil count <0.50 x 103 cells/μL;

               -  Platelet count <25 x 103 cells/μL;

               -  Total bilirubin >=3 mg/dL or >=34 mol/L (with the exception of subjects with
                  Gilbert's syndrome);

               -  Albumin <2.5g/dL;

               -  Creatinine Clearance (CrCl) <=50 mL/min (as estimated by Cockcroft and Gault).

               -  Serum ALT >=10 × ULN;

               -  Alpha-fetoprotein >200ng/mL.

          9. Prior exposure to NS5A inhibitors is prohibited but other classes and pegIFN/RBV are
             acceptable for treatment-experienced subjects;

         10. Use of any prohibited or restricted treatment at least is five half-lives or 14 days
             (whichever is longer) of the first dose of study drug (refer to section 4.5);

         11. History of cancer within 1 year of the screening visit with the exception of localized
             basal or squamous cell carcinoma;

         12. Any gastrointestinal disease or surgical procedure that may impact the absorption of
             study drug. (Subjects who have had cholecystectomy are permitted to enter the study);

         13. Known HIV infection;

         14. Confirmed, uncontrolled hypertension (any screening systolic blood pressure ≥ 160 mmHg
             or diastolic blood pressure ≥ 100 mmHg should be excluded);

         15. Presence or history of non-HCV chronic liver disease, including autoimmune hepatitis,
             alpha-1-antitrypsin deficiency, hemochromatosis, Wilson's disease, drug- or
             toxin-induced liver disease, alcohol-related liver disease, primary biliary cirrhosis
             and sclerosing cholangitis. Subjects with fatty liver and/or chronic hepatitis B virus
             in addition to HCV may be considered in the study;

         16. Uncontrolled seizures disorder;

         17. History of hemoglobinopathies, (e.g., thalassemia, sickle cell anemia, spherocytosis)
             or other cause of hemolytic anemia, including autoimmune causes;

         18. Active disease at screening visit known to cause significant alteration in immunologic
             function including hematologic malignancy, sarcoidosis or autoimmune disorder (e.g.,
             rheumatoid arthritis, systemic lupus erythematosis, leukemia, lymphoma, autoimmune
             thyroid disease, scleroderma, unstable psoriasis, and multiple sclerosis);

         19. Pregnant or lactating women or women who plan to become pregnant during the study;

         20. History of hypersensitivity to drugs with a similar biochemical structure to DCV or
             SOF or RBV;

         21. Any other criteria or known contraindication that would exclude the subject from
             receiving SOF or RBV (per the local label) or DCV;

         22. Inability to tolerate oral medication;

         23. Subjects, who in the opinion of the Investigator, are not suitable candidates for
             enrollment or who would not comply with the requirements of the study.