Randomized Phase II Study of Hepatitis C Immune Globulin Intravenous (Human), Civacir(TM), in Liver Transplantation

A Randomized, Open-Label Phase II Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Hepatitis C Immune Globulin Intravenous (Human), Civacir(TM), in Liver Transplant Recipients

A Phase 2 study to evaluate safety, pharmacokinetics and efficacy of Hepatitis C Immune Globulin Intravenous (human) [Civacir(TM)] for preventing or reducing the impact of recurrent HCV infection following liver transplantation.

Hepatitis C virus (HCV) infection is the leading single cause of liver transplantation (LT) in the US and Europe. Recurrence of HCV infection following LT is almost universal. There is currently no effective way to prevent post-transplantation HCV infection of the liver graft and related progression of HCV-related liver disease. This study is designed to evaluate a polyclonal human hepatitis C immune globulin (Civacir) given during and post liver transplantation for preventing or reducing the impact of recurrent HCV infection.

In this open-label trial, 2 subjects will be randomized to receive Civacir (standard of care treatment plus Civacir) for every 1 Control subject (standard of care treatment alone). Civacir recipients will receive 18 intravenous infusions over 24 weeks beginning at the time of liver transplantation.

Viral loads, liver enzyme assessments and liver biopsy assessments will be made at scheduled intervals during the study which will last for 48 weeks.

Inclusion Criteria:

• Male or female, 18 to 75 years of age.
• Written informed consent.
• Expectation of compliance with the protocol procedures.
• If female, have a negative pregnancy test within 3 days prior to randomization and use an acceptable method of contraception or be at least one year post-menopausal or surgically sterile.
• HCV infection identified by positive, quantifiable HCV-RNA test within 3 months prior to transplantation.
• First time liver transplant recipient.
• Primary, single organ recipient (deceased donor <65 years of age).
• Normal TSH.
• Subjects with a pre-LT diagnosis of hepatocellular carcinoma (HCC) may be enrolled provided: there is no evidence of extrahepatic spread, tumor is solitary and <5cm or there are up to three tumors <3 cm.
• Agree to receive study medication as outlined in the protocol and follow all study related procedures until the conclusion of their protocol participation.
• Agree to consume no alcohol during the entire study period.

Exclusion Criteria:

• Has received an investigational agent within the last six weeks prior to liver transplantation. Exceptions include Theraspheres for hepatocellular carcinoma or rifaximin.
• Known immunoglobulin A deficiency.
• Subject weighs more than 112.5 Kg (248 pounds).
• Known history of cancer, suspected cancer, or cancer therapy within 12 months prior to the administration of the investigational product, except for treatment for basal cell carcinoma, squamous cell carcinoma, cancer of the cervix in situ, early stage prostate cancer (Gleason's grade 1 or 2), or a history of malignancy where the risk of recurrence is >= 20% within 2 years. A significant exception is hepatocellular carcinoma with predefined acceptability (see inclusion criteria).
• Has any condition judged by the study physician to preclude participation in the study, including any psychological disorder, which might hinder compliance.
• History of use of immunosuppressive or immunomodulatory drugs within 3 months prior to randomization (except low-dose physiologic replacement glucocorticoid therapy (<=10 mg of prednisone or equivalent per day).
• Recipient of liver from a living donor.
• Subjects whose liver is obtained from a non-beating heart donor.
• Subjects scheduled to receive a split liver transplantation.
• Liver transplants that were obtained from donors across ABO incompatible blood type.
• Donor liver cold ischemic time greater than 20 hours.
• Donor liver is from a hepatitis C positive donor.
• Evidence of any other unresolved infection and any unresolved opportunistic infection requiring treatment.
• Serum creatinine level >2.0 times the upper limit of normal or advanced renal disease at screening.
• Neutrophil count <1500 cells/mm3, WBC>20,000 x 109/L, Hgb <8 g/dL, or platelet count <25,000 cells/mm3.
• Planned use of T-cell depleting antibody therapies.
• Hepatitis B (sAg, cAb IgM), hepatitis A (IgM) or HIV infection.
• History of autoimmune disease (SLE, scleroderma, RA, etc.).
• Women who are pregnant or breast feeding.
• The use of colony stimulating factor agents to facilitate subject's entry into study within 2 weeks of enrollment.
• History of severe psychiatric disease, especially depression.
• Seizure disorders uncontrolled by anticonvulsants (within the last 12 mos).
• History of severe cardiac disease, unhealed gastric or duodenal ulcer, or other significant medical disease that would put the subject at risk from the volume of the infusions or significant risk of bleeding from the underlying condition.
• Evidence of alcohol and/or drug abuse within 6 months of entry or inability/unwilling-ness to abstain from alcohol throughout entire course of treatment and follow-up.
• Concomitant medication with rifabutin, pyrazinamide, isoniazid, thalidomide, oxymetholone (Anadrol).
• History of thyroid disease poorly controlled on prescribed medications.
• History or other evidence of severe illness or any other conditions which would make the subject, in the opinion of the investigator, unsuitable for Civacir treatment.