Viral Kinetics, Interferon Stimulated Genes (ISGs) and mirRNA Among Subjects Infected With Different Hepatitis C Virus Genotypes During Therapy With Sofosbuvir and GS-5816
Condition: Chronic Hepatitis C
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Hepatitis, Chronic
Intervention: Sofosbuvir; GS-5816
Intervention description: An NS5B polymerase inhibitor that is already approved for use in combination with interferon and ribavirin for the treatment of HCV genotype 1 infection; An NS5A replication complex inhibitor with potent activity against most strains of hepatitis C virus.
Intervention MeSH terms: Sofosbuvir; Velpatasvir
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 72.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Oral Therapy; Liver Biopsy; Chronic Hepatitis C

Summary:

      Background:

      - Chronic hepatitis C is a serious liver disease. Current treatments have side effects. New
      drugs have been developed, but they work better in some people than others. Researchers want
      to learn why.

      Objective:

      - To learn why new hepatitis C drugs sometimes do not work. Also, to learn if these drugs are
      safe and how well they work in people with different virus strains.

      Eligibility:

      - Adults age 18 and older who are infected with hepatitis C virus genotypes 1-4 and who have
      either never been treated or treated previously with an interferon regimen (with or without
      ribavirin) that failed to clear the virus.

      Design:

        -  Participants will be screened with medical history and physical exam. They will have
           blood and urine tests and complete questionnaires.

        -  Participants will have a Fibroscan, an ultrasound that measures liver stiffness and
           other liver scans. They will have an electrocardiogram.

        -  Eligible participants will have a liver biopsy.

        -  Participants will be admitted to the Clinical Center. They will have a physical exam and
           blood tests, and complete questionnaires.

        -  They will take the first study drug dose as a tablet taken once daily.

        -  Participants will take the drug at home for 12 weeks.

        -  Participants will have 6 study visits. They will have blood and vital signs taken, and
           complete questionnaires.

        -  At week 4, participants will have another liver biopsy.

        -  After their last drug dose, participants will have 5 follow-up visits. They will have
           blood and vital signs taken, and complete questionnaires. They will discuss their
           medications and side effects. They may have another Fibroscan.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Subjects must meet all of the following inclusion criteria to be eligible for participation
        in this study.

          -  Willing and able to provide written informed consent.

          -  Male or female, age greater than or equal to18 years.

          -  Body mass index (BMI) greater than or equal to 18 kg/m^2.

          -  HCV RNA greater than or equal to10^4 IU/mL at Screening

          -  HCV genotypes 1a, 1b, 2, 3 or 4 at screening

          -  Confirmation of chronic HCV infection documented by either:

               -  A positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping
                  test at least 6 months prior to the Baseline/Day 1 visit, or

               -  A liver biopsy performed within 12 weeks prior to the Baseline/Day 1 visit with
                  evidence of chronic HCV infection. A prior biopsy would be acceptable if
                  performed with 12 weeks AND liver tissue stored in RNALater was available.

          -  Screening ECG without clinically significant abnormalities.

          -  Subjects must have the following laboratory parameters at screening:

               -  ALT less than or equal to 10 times the upper limit of normal (ULN)

               -  AST less than or equal to 10 times ULN

               -  Direct bilirubin less than or equal to 1.5 ULN

               -  Platelets > 70,000

               -  HbA1c less than or equal to8.5%

               -  eGFR greater than or equal to 60 mL /min, as calculated by the CKD-EPI equation.

               -  Hemoglobin greater than or equal to 10g/dL.

               -  Albumin greater than or equal to 3g/dL

               -  INR less than or equal to 1.5 x ULN unless subject has known hemophilia or is
                  stable on an anticoagulant regimen affecting INR.

          -  A female subject is eligible to enter the study if it is confirmed that she is:

               -  Not pregnant or nursing

               -  Of non-childbearing potential (i.e., women who have had a hysterectomy, have both
                  ovaries removed or medically documented ovarian failure, or are postmenopausal
                  women > 50 years of age with cessation (for greater than or equal to 12 months)
                  of previously occurring menses),

        OR

          -  Of childbearing potential (i.e., women who have not had a hysterectomy, have not had
             both ovaries removed, and have not had medically documented ovarian failure). Women
             less than or equal to 50 years of age with amenorrhea will be considered to be of
             childbearing potential. These women must have a negative serum pregnancy test at
             Screening and a negative urine pregnancy test on the Baseline/Day 1 visit prior to
             randomization. They must also agree to one of the following from 3 weeks prior to
             Baseline/Day 1 until 90 days after last dose of study drug:

               -  Complete abstinence from intercourse. Periodic abstinence from intercourse (e.g.,
                  calendar, ovulation, symptothermal, post-ovulation methods) is not permitted.

               -  Consistent and correct use of 1 of the following methods of birth control listed
                  below in addition to a male partner who correctly uses a condom from the date of
                  Screening until 90 days after last dose of study drug:

                    -  intrauterine device (IUD) with a failure rate of < 1% per year

                    -  female barrier method: cervical cap or diaphragm with spermicidal agent

                    -  tubal sterilization

                    -  vasectomy in male partner

                    -  hormone-containing contraceptive:

                         -  implants of levonorgestrel

                         -  injectable progesterone

                         -  oral contraceptives (either combined or progesterone only)

                         -  contraceptive vaginal ring

                         -  transdermal contraceptive patch

                              -  All male study participants must agree to consistently and
                                 correctly use a condom, while their female partner agrees to use 1
                                 of the methods of birth control listed above, from the date of
                                 Screening until 90 days after last dose of study drug.

                              -  Male subjects must agree to refrain from sperm donation from 90
                                 days after their last dose of study 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, including all required post treatment visits.

        EXCLUSION CRITERIA:

        Subjects who meet any of the following exclusion criteria will not to be enrolled in this
        study.

          -  Current or prior history of any of the following:

               -  Clinically-significant illness (other than HCV) or any other major medical
                  disorder that may interfere with subject treatment, assessment or compliance with
                  the protocol; subjects currently under evaluation for a potentially
                  clinically-significant illness (other than HCV) are also excluded.

               -  Gastrointestinal disorder or post-operative condition that could interfere with
                  the absorption of the study drug.

               -  Difficulty with blood collection and/or poor venous access for the purposes of
                  phlebotomy.

               -  Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal
                  hemorrhage).

               -  Solid organ transplantation.

               -  Significant pulmonary disease, significant cardiac disease or porphyria.

               -  Psychiatric hospitalization, suicide attempt, and/or a period of disability as a
                  result of their psychiatric illness within the last 5 years. Subjects with
                  psychiatric illness (without the prior mentioned conditions) that is
                  well-controlled on a stable treatment regimen for at least 12 months prior to
                  randomization or has not required medication in the last 12 months may be
                  included.

               -  Malignancy within 5 years prior to screening, with the exception of specific
                  cancers that are entirely cured by surgical resection (basal cell skin cancer,
                  etc). Subjects under evaluation for possible malignancy are not eligible.

               -  Significant drug allergy (such as anaphylaxis or hepatotoxicity).

          -  Any prior treatment with a direct acting antiviral agent (protease inhibitors, NS5A
             inhibitors and NS5B polymerase inhibitors/non-nucleoside polymerase inhibitors.)

          -  Pregnant or nursing female or male with pregnant female partner.

          -  Chronic liver disease of a non HCV etiology (e.g., hemochromatosis, Wilson s disease,
             alfa 1 antitrypsin deficiency, cholangitis).

          -  Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).

          -  Clinically-relevant drug abuse within 12 months of screening. A positive drug screen
             will exclude subjects unless it can be explained by a prescribed medication; the
             diagnosis and prescription must be approved by the investigator.

          -  Use of any prohibited concomitant medications as described within 21 days of the
             Baseline/Day 1 visit; this washout period does not apply to PPIs, which can be taken
             up to 7 days before baseline Day 1.

          -  Use of antiviral medications within the last 30 days.

          -  Chronic use of systemically administered immunosuppressive agents (e.g., prednisone
             equivalent > 10 mg/day).

          -  Known hypersensitivity to GS-5816, SOF, or formulation excipients.