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
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      Up to 140 patients with chronic hepatitis C, genotypes 1-4, who were never treated or
      previously treated but failed a course of therapy with any interferon and ribavirin
      combination regimen will be eligible to be enrolled into this pilot study to evaluate the
      combination of sofosbuvir and GS-5816 as a fixed dose tablet to improve response to antiviral
      therapy. To enrich the study population with subjects with a greater likelihood of
      virological relapse after stopping therapy, we plan to enroll a minimum of 60%
      treatment-experienced subjects and 50% with cirrhosis. These two drugs inhibit key enzymes
      that are necessary for viral replication. Sofosbuvir, an NS5B polymerase inhibitor is already
      approved for use in combination with interferon and ribavirin for the treatment of HCV
      genotype 1 infection. GS-5816 is an NS5A replication complex inhibitor with potent activity
      against most strains of hepatitis C virus. Combining these two agents into a single pill
      should improve patient compliance and improve tolerability because interferon and ribavirin
      will not be part of the regimen. After medical evaluation and liver biopsy, patients will
      receive combination therapy with sofosbuvir and GS-5816 one pill a day for 12 weeks. The
      baseline liver biopsy is necessary to assess the amount of liver damage caused by the HCV and
      to measure expression of genes associated with clearance of HCV. Blood samples will be
      collected to monitor safety and response to therapy and for research purposes. HCV RNA levels
      will be monitored frequently for the initial 4 weeks and then at monthly intervals for the
      remaining 8 weeks of antiviral therapy. All subjects will undergo a second liver biopsy, 4
      weeks after starting therapy. The second biopsy is being performed for research purposes so
      investigators can determine specifically which liver genes are associated with failure of
      therapy (and response to therapy). Subjects who refuse the second liver biopsy will continue
      to receive SOF/GS-5816 treatment for the planned 12 week duration Patients in whom serum HCV
      RNA is greater than or equal to lower limit of quantification (LLOQ) after 2 consecutive HCV
      RNA < LLOQ or who have a confirmed > 1 log10 increase from nadir will discontinue therapy
      (because continuing therapy is considered futile i.e. it is unlikely to work). The major
      endpoints will be changes in interferon stimulated gene and protein expression in the liver
      and changes in HCV RNA levels in liver and serum between baseline and 4 weeks and rates of
      sustained virologic response at post-treatment week 12. Secondary endpoints will be safety
      and sustained virologic response at post-treatment week 24 weeks.
    

Intervention name(s): Sofosbuvir; GS-5816
Intervention type(s): Drug; Drug
Intervention description(s): 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
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Oral Therapy; Liver Biopsy; Chronic Hepatitis C