Efficacy of Sofosbuvir With Ribavirin Administered Pre-Transplant in Preventing Hepatitis C Virus (HCV) Recurrence Post-Transplant

An Open-Label Study to Explore the Clinical Efficacy of GS-7977 With Ribavirin Administered Pre-Transplant in Preventing Hepatitis C Virus (HCV) Recurrence Post-Transplant

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.

Study Overview

• Status: Completed
• Conditions: Hepatocellular Carcinoma; Hepatitis C
• Intervention / Treatment: Drug: Sofosbuvir; Drug: Ribavirin

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 2

Contacts and Locations

Study Locations

• New Zealand
  • Auckland, New Zealand
    • Auckland Clinical Studies
• Spain
  • Pamplona, Spain, 31008
    • Liver Unit Clinica University de Navara
• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center-The Pfleger Liver Institute
    • San Diego, California, United States, 92103
      • UC San Diego
    • San Francisco, California, United States, 94143-0124
      • University of California, San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80010
      • University of Colorado
  • Florida
    • Miami, Florida, United States, 33102-5405
      • University of Miami
    • Miami Beach, Florida, United States, 33140
      • Mount Sinai Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Burlington, Massachusetts, United States, 01805
      • Lahey Clinic Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Missouri
    • St. Louis, Missouri, United States, 63110-0250
      • St. Louis University Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor Health Care System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SOF+RBV; Sofosbuvir plus ribavirin for up to 48 weeks or until time of transplant, whichever occurs first.	Drug: Sofosbuvir; Sofosbuvir 400 mg (2 x 200 mg tablets) administered orally once daily; Other Names: Sovaldi®; GS-7977; PSI-7977; Drug: Ribavirin; 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Posttransplant Virologic Response (pTVR) at Posttransplant Week 12	pTVR was defined as HCV RNA < the lower limit of quantification (LLOQ, ie, 25 mL/IU) at Week 12 after transplant.	Posttransplant Week 12
Percentage of Participants Experiencing Any Adverse Event Leading to Permanent Discontinuation of Sofosbuvir Prior to Receiving Transplant		Up to 48 weeks prior to transplant
Percentage of Participants With Graft Loss Following Transplant		Up to 48 weeks following transplant
Number of Participants Who Died	Treatment-emergent deaths were those that occurred while taking study drug or to the minimum of 1) date of transplantation, 2) retreatment 1st dose date, or 3) last dose date + 30 days.; Only those participants who underwent liver transplantation were analyzed for death post-transplantation.	Up to 48 weeks following transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Posttransplant Virologic Response (pTVR) Through Posttransplant Week 48	pTVR was defined as HCV RNA < the lower limit of quantification (LLOQ, ie, 25 mL/IU) at the relevant time point after transplant.	Up to 48 weeks following transplant
Percentage of Participants With HCV RNA < LLOQ (ie, 25 mL/IU) During Treatment Through Week 48		Up to 48 weeks prior to transplant
HCV RNA and Change From Baseline in HCV RNA Through Week 8		Up to 8 weeks prior to transplant
Proportion of Participants With Virologic Failure Prior to Transplant	Virologic failure (VF) in the pretransplant phase was defined by: Breakthrough (HCV RNA ≥ 25 IU/ml after having previously had HCV RNA < 25 IU/ml, while on treatment); Rebound (breakthrough or > 1 log10 IU/ml increase in HCV RNA from nadir while on treatment); Non-response (HCV RNA ≥ 25 IU/ml through 8 weeks of treatment); Pre-transplant relapse (HCV RNA ≥ 25 IU/ml during the Pre-Transplant off-treatment follow-up period after having achieved HCV RNA < 25 IU/ml at last observed HCV RNA on treatment)	Up to 48 weeks prior to transplant

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Study Director: Jill Denning, MA, Gilead Sciences

Publications and helpful links

General Publications

• Babusis D, Curry MP, Kirby B, Park Y, Murakami E, Wang T, Mathias A, Afdhal N, McHutchison JG, Ray AS. Sofosbuvir and Ribavirin Liver Pharmacokinetics in Patients Infected with Hepatitis C Virus. Antimicrob Agents Chemother. 2018 Apr 26;62(5):e02587-17. doi: 10.1128/AAC.02587-17. Print 2018 May.
• Curry MP, Forns X, Chung RT, Terrault NA, Brown R Jr, Fenkel JM, Gordon F, O'Leary J, Kuo A, Schiano T, Everson G, Schiff E, Befeler A, Gane E, Saab S, McHutchison JG, Subramanian GM, Symonds WT, Denning J, McNair L, Arterburn S, Svarovskaia E, Moonka D, Afdhal N. Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an open-label study. Gastroenterology. 2015 Jan;148(1):100-107.e1. doi: 10.1053/j.gastro.2014.09.023. Epub 2014 Sep 28.

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: March 5, 2012
• First Submitted That Met QC Criteria: March 19, 2012
• First Posted (Estimate): March 21, 2012

Study Record Updates

• Last Update Posted (Estimate): July 27, 2016
• Last Update Submitted That Met QC Criteria: June 16, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: transplant; HCC; hepatocellular carcinoma; Hepatitis; Chronic
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Disease Attributes; Digestive System Neoplasms; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Liver Neoplasms; Enterovirus Infections; Picornaviridae Infections; Hepatitis; Carcinoma, Hepatocellular; Hepatitis A; Hepatitis C; Recurrence; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Sofosbuvir; Ribavirin
• Other Study ID Numbers: P7977-2025