Civacir® Polyclonal Immune Globulin (IgG) to Prevent Hepatitis C Virus (HCV) Recurrence in Liver Transplant Patients.

A Multi-Center, Randomized, Prospective, Open-Label Phase III Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Hepatitis C Immune Globulin Intravenous (Human), Civacir®, in Orthotopic Liver Transplant Recipients

The purpose of this study is to test the safety and efficacy of Civacir® to prevent the recurrence of Hepatitis C Virus (HCV) after liver transplant.

Study Overview

• Status: Completed
• Conditions: Liver Cirrhosis; Hepatitis, Viral, Human; Hepatocellular Carcinoma; Hepatitis C Infection; Viruses
• Intervention / Treatment: Biological: Civacir® 10%

Detailed Description

Civacir® 10%, Hepatitis C Immune Globulin Intravenous (Human) is a high-titer human polyclonal immune globulin (IgG) containing a diversity of antibodies that target and bind the hepatitis C virus (HCV) to prevent infection. Subjects who reduce their viral load to less than 100 IU/ml HCV RNA through up to 24 weeks of antiviral therapy prior to liver transplant are enrolled in the study. There is no requirement to reach undetectable virus prior to transplant as the function of Civacir® is to neutralize any remaining virus in circulation.

Subjects randomized to Civacir® treatment arms receive study drug infusions starting on the day of liver transplant followed by 15 doses over a 10 week period to prevent the recurrence of quantifiable Hepatitis C Virus (HCV) after liver transplant. The study will evaluate dosing arms ranging from 200 mg/kg to 300 mg/kg compared to a control arm. For the primary endpoint, efficacy is defined as persistent viral load suppression maintaining HCV RNA levels below the lower limit of quantitation as determined by central laboratory Polymerase Chain Reaction (PCR) at 22 weeks post-liver transplant and then at 34 weeks post-liver transplant to demonstrate durability of effect.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California / Keck Hospital
    • San Francisco, California, United States, 94143
      • University of California San Francisco
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine
    • Orlando, Florida, United States, 32804
      • Florida Hospital Transplant Institute
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Piedmont Hospital
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Chandler Medical Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Burlington, Massachusetts, United States, 01805
      • Lahey Hospital
  • New York
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
    • New York, New York, United States, 10029
      • The Mount Sinai Medical Center
    • New York, New York, United States, 10032
      • Columbia University College of Physicians and Surgeons
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Tennessee
    • Memphis, Tennessee, United States, 38104
      • Methodist University Hospital
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Houston, Texas, United States, 77030
      • Houston Methodist
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
    • Houston, Texas, United States, 77030
      • Advanced Liver Therapies / St. Luke's Episcopal Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah Health Sciences Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Written informed consent obtained prior to any study-specific assessments and within 3 months (reconsent) of orthotopic liver transplantation (OLT).
• HCV Genotype 1 through 6 Infection.
• Subjects in the beginning of a new antiviral therapy regimen (regardless of prior treatment failures) for up to and including 24 weeks prior to the day of OLT.
• Most recent evidence within the last 4 weeks that HCV RNA is <100 IU/mL. Subjects may be randomized based on local lab HCV RNA.
• Male and female subjects (age 18-80 years).
• Subject weight under 250 pounds.
• Stable patient in a condition which in the opinion of the investigator would permit safe participation in the study.

Exclusion Criteria:

• Re-transplantation due to viral recurrence.
• Positive HIV or HBV test within 90 days prior to transplantation.
• Most recent PCR test indicating HCV RNA ≥100 IU/mL within 4 weeks of OLT.
• Subjects having received organs from HCV positive donors.
• Serum creatinine level >2.5 times the upper limit of normal or advanced renal disease at screening.
• Pregnancy or single contraceptive measure or lactation period (females only).
• Known intolerance to immunoglobulins or comparable substances (e.g. vaccination reaction).
• Known absolute Immunoglobulin A (IgA) deficiency.
• Known intolerance to proteins of human origin.
• Participation in another clinical trial within 90 days before signing Informed Consent Form (ICF) or during the study (observational/ non-interventional and 988 studies allowed), and/or previous participation in 988 study (except for Study 988 screen failures).
• Active drug and/or alcohol abuse.
• Inability or lacking motivation to participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Observational Control; Subjects who attain HCV RNA <100 IU/ml and are randomized to the control arm will receive standard post-transplant immunosuppressant therapy and be followed for a 34 week period.
Experimental: Civacir® 10% at 200 mg/kg dose; Subjects who attain HCV RNA <100 IU/ml and are randomized to the Civacir 200 mg/kg treatment arm will receive Civacir® before liver transplant, followed by 15 infusions over a 10 week regimen, with standard post-transplant immunosuppressant therapy. Civacir® treated subjects will be followed up to 34 weeks post-transplant.	Biological: Civacir® 10%; The active ingredient is Human Immunoglobulin G (IgG) which is a normal constituent purified from human source plasma containing a diversity of antibodies targeting the Hepatitis C Virus.; Other Names: Civacir®; Hepatitis C Immune Globulin Intravenous (Human); human polyclonal immune globulin (IgG); HCIg
Experimental: Civacir® 10% at 300 mg/kg dose; Subjects who attain HCV RNA <100 IU/ml and are randomized to the Civacir® 300 mg/kg treatment arm will receive Civacir® before liver transplant, followed by 15 infusions over a 10 week regimen, with standard post-transplant immunosuppressant therapy. Civacir® treated subjects will be followed up to 34 weeks post-transplant.	Biological: Civacir® 10%; The active ingredient is Human Immunoglobulin G (IgG) which is a normal constituent purified from human source plasma containing a diversity of antibodies targeting the Hepatitis C Virus.; Other Names: Civacir®; Hepatitis C Immune Globulin Intravenous (Human); human polyclonal immune globulin (IgG); HCIg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the efficacy of Civacir® in preventing post-transplant HCV recurrence at 22 weeks post transplant	The primary objective is to assess the effect of administering Civacir® anti-HCV immunoglobulin therapy on prevention of orthotopic liver transplant (OLT) HCV recurrence, as measured by the proportion of subjects with unquantifiable HCV RNA levels at 22 weeks post-OLT, compared to the control group (not treated with Civacir® and considered standard of care).	22 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the efficacy of Civacir® in preventing post-transplant HCV recurrence at 4 and 34 weeks post transplant	Evaluate the proportion of subjects with unquantifiable HCV RNA, as measured quantitatively by PCR at 4 and 34 weeks post-OLT, for assessing the durability of effect.	34 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the biochemical response of Civacir® in preventing post-transplant HCV recurrence at 22 and 34 weeks post transplant	Evaluate the biochemical response at 22 and 34 weeks post-transplant: the proportions of subjects with normal ALT, AST, total bilirubin and alkaline phosphates at 22 and 34 weeks.	34 weeks
Evaluate the safety of Civacir® in preventing post-transplant HCV recurrence up to 34 weeks post transplant	Evaluate the safety of Civacir® in the treatment of subjects with HCV undergoing liver transplantation by the number of adverse events including safety laboratory parameters.	34 weeks
Evaluate the pharmacokinetics of Civacir® up to 34 weeks post transplant	Evaluate the pharmacokinetics of Civacir® following intravenous infusion(s).	34 weeks

Collaborators and Investigators

• Sponsor: Biotest Pharmaceuticals Corporation
• Investigators: Principal Investigator: Norah Terrault, MD, MPH, University of California, San Francisco

Publications and helpful links

General Publications

• Everson GT, Terrault NA, Lok AS, Rodrigo del R, Brown RS Jr, Saab S, Shiffman ML, Al-Osaimi AM, Kulik LM, Gillespie BW, Everhart JE; Adult-to-Adult Living Donor Liver Transplantation Cohort Study. A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis C after liver transplantation. Hepatology. 2013 May;57(5):1752-62. doi: 10.1002/hep.25976. Epub 2013 Jan 17.
• Davis GL, Nelson DR, Terrault N, Pruett TL, Schiano TD, Fletcher CV, Sapan CV, Riser LN, Li Y, Whitley RJ, Gnann JW Jr; Collaborative Antiviral Study Group. A randomized, open-label study to evaluate the safety and pharmacokinetics of human hepatitis C immune globulin (Civacir) in liver transplant recipients. Liver Transpl. 2005 Aug;11(8):941-9. doi: 10.1002/lt.20405.

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: March 4, 2013
• First Submitted That Met QC Criteria: March 4, 2013
• First Posted (Estimate): March 5, 2013

Study Record Updates

• Last Update Posted (Actual): March 15, 2017
• Last Update Submitted That Met QC Criteria: March 14, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: HCV Liver Transplant Immunoglobulin PCR SVR
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Enterovirus Infections; Picornaviridae Infections; Fibrosis; Hepatitis; Hepatitis A; Hepatitis C; Liver Cirrhosis; Hepatitis, Viral, Human; Physiological Effects of Drugs; Immunologic Factors; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous; gamma-Globulins; Rho(D) Immune Globulin; Immunoglobulin G
• Other Study ID Numbers: 988

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED