Clinical trial NCT01559844: Efficacy of Sofosbuvir With Ribavirin Administered Pre-Transplant in Preventing Hepatitis C Virus (HCV) Recurrence Post-Transplant
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatitis C
Hepatocellular Carcinoma
Keywords: Hepatitis
Chronic
hepatocellular carcinoma
HCC
transplant
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2012-03-21
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Percentage of Participants With Posttransplant Virologic Response (pTVR) at Posttransplant Week 12
timeFrame: Posttransplant Week 12
measure: Percentage of Participants Experiencing Any Adverse Event Leading to Permanent Discontinuation of Sofosbuvir Prior to Receiving Transplant
timeFrame: Up to 48 weeks prior to transplant
measure: Percentage of Participants With Graft Loss Following Transplant
timeFrame: Up to 48 weeks following transplant
measure: Number of Participants Who Died
timeFrame: Up to 48 weeks following transplant
Secondary outcomes:
measure: Percentage of Participants With Posttransplant Virologic Response (pTVR) Through Posttransplant Week 48
timeFrame: Up to 48 weeks following transplant
measure: Percentage of Participants With HCV RNA < LLOQ (ie, 25 mL/IU) During Treatment Through Week 48
timeFrame: Up to 48 weeks prior to transplant
measure: HCV RNA and Change From Baseline in HCV RNA Through Week 8
timeFrame: Up to 8 weeks prior to transplant
measure: Proportion of Participants With Virologic Failure Prior to Transplant
timeFrame: Up to 48 weeks prior to transplant
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Medical Center-The Pfleger Liver Institute
state: California
city: San Diego
country: United States
facility: UC San Diego
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Clinic Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: St. Louis
country: United States
facility: St. Louis University Hospital
state: Missouri
city: New York
country: United States
facility: Columbia University
state: New York
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Dallas
country: United States
facility: Baylor Health Care System
state: Texas
city: Auckland
country: New Zealand
facility: Auckland Clinical Studies
city: Pamplona
country: Spain
facility: Liver Unit Clinica University de Navara
Study officials:
affiliation: Gilead Sciences
name: Jill Denning, MA
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.