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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01559844
Recruitment Status : Completed
First Posted : March 21, 2012
Results First Posted : May 28, 2015
Last Update Posted : July 27, 2016
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Tracking Information
First Submitted Date  ICMJE March 5, 2012
First Posted Date  ICMJE March 21, 2012
Results First Submitted Date  ICMJE May 12, 2015
Results First Posted Date  ICMJE May 28, 2015
Last Update Posted Date July 27, 2016
Study Start Date  ICMJE March 2012
Actual Primary Completion Date May 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 16, 2016)
  • Percentage of Participants With Posttransplant Virologic Response (pTVR) at Posttransplant Week 12 [ Time Frame: Posttransplant Week 12 ]
    pTVR was defined as HCV RNA < the lower limit of quantification (LLOQ, ie, 25 mL/IU) at Week 12 after transplant.
  • Percentage of Participants Experiencing Any Adverse Event Leading to Permanent Discontinuation of Sofosbuvir Prior to Receiving Transplant [ Time Frame: Up to 48 weeks prior to transplant ]
  • Percentage of Participants With Graft Loss Following Transplant [ Time Frame: Up to 48 weeks following transplant ]
  • Number of Participants Who Died [ Time Frame: Up to 48 weeks following transplant ]
    • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 19, 2012)
Determination of post-transplant virological response [ Time Frame: 36 Weeks ]
To determine if the administration of a combination of GS 7977 and ribavirin to HCV-infected subjects with hepatocellular carcinoma (HCC) meeting the MILAN criteria prior to undergoing liver transplantation for up to 24 weeks can prevent post-transplant re-infection as determined by a sustained post-transplant virological response (HCV RNA <LLoQ) at 12 weeks post-transplant.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 12, 2015)
  • Percentage of Participants With Posttransplant Virologic Response (pTVR) Through Posttransplant Week 48 [ Time Frame: Up to 48 weeks following transplant ]
    pTVR was defined as HCV RNA < the lower limit of quantification (LLOQ, ie, 25 mL/IU) at the relevant time point after transplant.
  • Percentage of Participants With HCV RNA < LLOQ (ie, 25 mL/IU) During Treatment Through Week 48 [ Time Frame: Up to 48 weeks prior to transplant ]
  • HCV RNA and Change From Baseline in HCV RNA Through Week 8 [ Time Frame: Up to 8 weeks prior to transplant ]
  • Proportion of Participants With Virologic Failure Prior to Transplant [ Time Frame: Up to 48 weeks 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)
Original Secondary Outcome Measures  ICMJE
 (submitted: March 19, 2012)
  • Determination of Sustained Viral Response (SVR) 12 [ Time Frame: 36 weeks ]
    To determine if the administration of a combination of GS 7977 and ribavirin to HCV-infected subjects with HCC meeting the MILAN criteria prior to undergoing liver transplantation can elicit a sustained viral response as determined by HCV RNA <LLoQ 12 weeks after the discontinuation of therapy (SVR12).
  • Assess safety and tolerability (discontinuation for AE, and treatment-emergent SAEs and Grade 3 and higher clinical and laboratory events) of a combination of GS‑7977 and ribavirin in HCV-infected subjects prior to undergoing liver transplantation [ Time Frame: 24 week on-treatment, 48 weeks follow up ]
    To evaluate the safety and tolerability of a combination of GS 7977 and ribavirin in HCV-infected subjects prior to undergoing liver transplantation
  • HCV Viral Kinetic [ Time Frame: 24 weeks ]
    To evaluate the HCV RNA viral kinetics during the treatment phase and following liver transplant and correlate results with the duration of study treatment prior to liver transplant (LT).
  • Presence of absence of liver HCV RNA [ Time Frame: 24 Weeks ]
    To explore the presence or absence of HCV RNA in the liver explants and correlate with plasma HCV RNA viral kinetics during therapy, plasma GS-7977 and metabolite exposure (if possible), duration of therapy, duration of plasma HCV RNA negativity.
  • Dynamics of non-tumor MELD score [ Time Frame: 24 Weeks ]
    To explore the dynamics of non-tumor MELD score during the study.
  • Determination of GS-7977 and metabolite concentration in liver explants [ Time Frame: 24 hours ]
    To determine concentrations of GS-7977 and metabolites (if suitable analytical methods can be developed) in the liver explants in a subset of subjects who cease GS-7977 therapy within 24 hours of liver transplantation.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy of Sofosbuvir With Ribavirin Administered Pre-Transplant in Preventing Hepatitis C Virus (HCV) Recurrence Post-Transplant
Official Title  ICMJE 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
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hepatitis C
  • Hepatocellular Carcinoma
Intervention  ICMJE
  • Drug: Sofosbuvir
    Sofosbuvir 400 mg (2 x 200 mg tablets) administered orally once daily
    Other Names:
    • GS-7977
    • PSI-7977
    • Sovaldi®
  • 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)
Study Arms  ICMJE Experimental: SOF+RBV
Sofosbuvir plus ribavirin for up to 48 weeks or until time of transplant, whichever occurs first.
Interventions:
  • Drug: Sofosbuvir
  • Drug: Ribavirin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 4, 2015)
61
Original Estimated Enrollment  ICMJE
 (submitted: March 19, 2012)
40
Actual Study Completion Date  ICMJE October 2014
Actual Primary Completion Date May 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE New Zealand,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01559844
Other Study ID Numbers  ICMJE P7977-2025
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Gilead Sciences
Study Sponsor  ICMJE Gilead Sciences
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Jill Denning, MA Gilead Sciences
PRS Account Gilead Sciences
Verification Date June 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP