Efficacy of Sofosbuvir With Ribavirin Administered Pre-Transplant in Preventing Hepatitis C Virus (HCV) Recurrence Post-Transplant
Condition: Hepatitis C; Hepatocellular Carcinoma
MeSH terms: Hepatitis A; Hepatitis C; Carcinoma, Hepatocellular; Hepatitis; Recurrence
Intervention: Sofosbuvir; Ribavirin
Intervention description: Sofosbuvir 400 mg (2 x 200 mg tablets) administered orally once daily; Ribavirin (RBV) tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75kg = 1000 mg and ≥ 75 kg = 1200 mg)
Intervention MeSH terms: Ribavirin; Sofosbuvir
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 61.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Hepatitis; Chronic; hepatocellular carcinoma; HCC; transplant

Summary:

      The primary objective is to determine if the administration of a combination of sofosbuvir
      (SOF; GS-7977; PSI-7977) and ribavirin (RBV) to HCV-infected adults with hepatocellular
      carcinoma (HCC) meeting the MILAN criteria prior to undergoing liver transplantation could
      prevent post-transplant re-infection as determined by a sustained post-transplant virological
      response (HCV RNA < LLoQ) at 12 weeks post-transplant.

      Participants will enroll in the pretransplant treatment phase (24 or 48 weeks). Participants
      enrolling for 24 weeks in the pretransplant treatment phase may receive treatment for up to
      an additional 24 weeks in the pretransplant retreatment phase. Participants enrolling for 48
      weeks in the pretransplant treatment will have a second baseline at Week 24 for combined
      analysis in the pretransplant retreatment phase.

      Participants who undergo liver transplant will stop all study drug 24 hours prior to
      transplant, and enter a 48-week follow-up phase to monitor for recurrent HCV infection.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Willing and able to provide written informed consent

          2. Males or females, age > 18 years old

          3. Males must agree to consistently and correctly use a condom while their female partner
             agrees to use an approved form of birth control from the date of screening until 7
             months after their last dose of ribavirin.

          4. Confirmation of chronic HCV infection documented by at least one measurement of serum
             HCV RNA above the LLOQ measured at screening, and at least one of the following:

               -  Positive anti-HCV antibody test, HCV RNA or HCV genotyping test at least 6 months
                  prior to the baseline/Day 1 visit together with positive HCV RNA test and
                  anti-HCV antibody at the time of screening, or

               -  Positive HCV RNA test and anti-HCV antibody test at the time of screening
                  together with either a liver biopsy consistent with chronic HCV infection (or a
                  liver biopsy performed before enrollment with evidence of chronic HCV infection,
                  such as the presence of fibrosis)

          5. HCV RNA > 10^4 IU/mL at screening

          6. Patients meeting the MILAN criteria undergoing liver transplant for HCC secondary to
             HCV with a MELD of < 22 and a HCC weighted MELD of ≥ 22.

          7. Child-Pugh Score (CPT) ≤ 7

          8. Planned management of the subject to meet United Network for Organ Sharing (UNOS)
             criteria, with imaging studies made available for review if required.

          9. Has not been treated with any investigational drug or device within 30 days of the
             screening visit.

        Exclusion Criteria:

          1. Females of child-bearing potential who is pregnant or nursing

          2. Prior exposure to a direct-acting antiviral targeting the HCV nonstructural (NS)5B
             polymerase

          3. Any transplant patient who has agreed to a liver transplant from a live donor.

          4. Participants requiring planned induction therapy with biologics posttransplantation or
             with a posttransplantation immunosuppressive regimen not consistent with the following
             within the first 12 weeks posttransplant:

               -  Solumedrol/Prednisone (tapering over approximately 7 days)

               -  Tacrolimus (maintaining a serum level of 5 12 ng/mL)

               -  Mycophenolate mofetil (up to 2 g/day)

               -  Introduction of new maintenance immunosuppressants different from the above list
                  is disallowed except in consultation during the first 12 weeks posttransplant

          5. Current, uncontrolled ascites, variceal hemorrhage, hepatic encephalopathy,
             hepatorenal syndrome and hepatopulmonary syndrome, among other signs of decompensated
             cirrhosis.

          6. Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson's disease,
             alpha-1 antitrypsin deficiency, cholangitis)

          7. Infection with hepatitis B virus (HBV) or HIV

          8. Contraindications to RBV therapy

          9. Chronic use of systemically administered immunosuppressive agents (eg, prednisone
             equivalent > 10 mg/day) in the pretransplant treatment period.

         10. History of previous solid organ transplantation

         11. Evidence of renal impairment (CLcr < 60 mL/min) calculated by the Cockcroft-Gault
             equation.

         12. History or current evidence of psychiatric illness, immunologic disorder,
             hemoglobinopathy, pulmonary or cardiac disease, porphyria, or poorly controlled
             diabetes, cancer other than HCC, or a history of malignancy that in the opinion of the
             investigator makes the patient unsuitable for the study. Patients with clinical signs
             or symptoms of acute pancreatitis with elevated lipase (at Screening or during the
             screening period)

         13. Known hypersensitivity to RBV, the study investigational medicinal product, the
             metabolites, or formulation excipients

         14. History of having received any systemic antineoplastic (including sorafenib) or
             immunomodulatory treatment (including radiation) within 6 months prior to the first
             dose of study drug or the expectation that such treatment will be needed at any time
             during the study (excluding a local regional therapy such as TACE).

         15. Treatment with Transcatheter arterial chemoembolization (TACE) or radio frequency
             ablation (RFA) within 30 days prior to the first dose.

         16. Participation in a clinical study with an investigational drug, biologic, or device
             within 3 months prior to first dose administration at the baseline/Day 1 Visit.