Placebo Controlled Evaluation of the Cell Mediated Immune Response of Cirrhotic Subjects to Zostavax™
Placebo Controlled Evaluation of the Cell Mediated Immune Response of Cirrhotic Subjects to Zostavax™
Study Design:

 Double-blinded, placebo controlled study of the efficacy of Zostavax in cirrhosis.

 Subjects will receive either Zostavax or placebo and will be followed for four months.

 Hypothesis:

 The investigators hypothesize Zostavax would induce cell-based immunity in cirrhotic patients
 like that seen in elderly patients.
Study aim, background, and design

 Herpes Zoster (Shingles) is a major cause of pain and expense to the elderly and chronically
 ill. The incidence is estimated at 3 in 1,000 patients. Zostavax™ is a high dose, live
 varicella vaccine that has been validated in very large placebo control trials to reduce the
 incidence of Herpes Zoster rash and post herpetic neuralgia in patients over 50 years of age.
 Additionally the vaccine has been shown to increase quality of life in these patients.
 Symptomatic Herpes Zoster rates are particularly high post liver transplant with the 3-, 5-,
 and 10-year actuarial rates of Herpes Zoster of 3%, 10%, 14%, and 18%, respectively. Zostavax
 is currently recommended for patients prior to solid organ transplantation with no adult data
 in liver transplant candidates to support that practice. And Although cirrhosis has been
 acknowledged as a risk factor for symptomatic Herpes Zoster, there is no published data on
 the efficacy of Zostavax in chronically ill cirrhotic adults pre-transplantation. In
 particular, it is not known whether or not chronically ill cirrhotic patients demonstrate the
 appropriate age related cell-mediated immune response seen in the original Zostavax trials.

 Procedure

 The study will be divided into 3 parts: Screening, Day 1 (or administration of study drug),
 and Follow Up.

 There will be a 4 week screening period. The following procedures will occur in Screening:

 Sign consent History and physical exam Inclusion and exclusion review Collection of
 concomitant medications

 The screening visit may occur on the same day as the Day 1 visit. The following procedures
 will occur on Day 1:

 Confirm eligibility Predose lab collection: Interferon-G Enzyme-Linked Immunospot Assay
 (ELISPOT), GPELISA, VZV Glycoprotein Enzyme-Linked Immunosorbent Assay (also known as
 Varicella Zoster antibody titre), and Urine pregnancy test for women of childbearing
 potential Randomize the subject Administer study drug - either Zostavax vaccine or placebo

 Follow Up Period:

 Month 1 - phone call and collection of adverse events (AEs) and concomitant medications 6
 week visit - post dose lab collection: Interferon-G Enzyme-Linked Immunospot Assay (ELISPOT)
 and GPELISA, VZV Glycoprotein Enzyme-Linked Immunosorbent Assay (also known as Varicella
 Zoster antibody titre) Months 2, 3 and 4 - phone call and collection of AEs and concomitant
 medications

 Laboratory Tests: The Zoster antibody titer will be run in the Tulane Medical Center Lab and
 will result in Meditech. The cell mediated immune response lab (ELISPOT) is not a standard
 lab at Tulane Medical Center. This will be run in Tulane Medical School by a research
 scientist, whose personal lab has the capabilities to do this special assay.

 Telephone Calls: After injection, the subject will follow up with the Investigator as
 clinically indicated. A study team member will call the subject once a month for 4 months. A
 standardized approach will be used for every subject. The subject will be asked about
 concomitant medications and adverse events such as rashes, fevers, hospitalizations,
 injection site reactions, signs of hepatic decompensation including ascites, confusion,
 bleeding, and any other physician office visits.

 After all of the subjects have completed and assays resulted, the study will be unblinded.
 The subjects who received placebo will be offered Zostavax vaccine at no cost and will be
 offered the chance to go into the Follow Up Period described above. The placebo subjects do
 not have to participate in the Follow Up Period to receive the Zostavax vaccine. The subjects
 can opt to receive the vaccine or not receive the vaccine or receive the vaccine and give
 blood on day 1 and again at 6 weeks and also have the option to get the monthly calls for 4
 months.

 Labs: Pre-vaccination and 6 week post-vaccination measure of varicella immune response
 Interferon-G Enzyme-Linked Immunospot Assay (ELISPOT) - performed at Tulane Medical School
 Laboratory.

 GPELISA, VZV Glycoprotein Enzyme-Linked Immunosorbent Assay (Varicella Zoster antibody titre)
 - performed at Tulane Medical Center Laboratory.

 There will be approximately 20 cc of blood drawn per lab collection. Total volume of blood
 drawn for the study is 40cc.

 Four month post dose monitoring: telephone contact occurring once a month for 4 months to
 monitor for adverse events and concomitant medications.

 All placebo subjects will be offered complimentary Zostavax vaccine after study closed and
 un-blinded. See detailed explanation in Procedure.

 Randomization:

 Thirty subjects will be randomized via sealed envelope system to either vaccine or placebo.
 Fifteen envelopes will have the Zostavax designation and fifteen envelopes will have the
 placebo designation. The subject will choose one of the sealed envelopes for treatment. The
 sealed envelope is taken to the pharmacist who will open the envelope and dispense the
 treatment as indicated. Only the pharmacist is unblinded to the treatment.

 Adverse events:

 Adverse Events will be collected from Day 1 until the end of the subject's participation.
 Events of interest are listed below.

 Clinical Herpes Zoster Injection site reaction Hospitalization (any cause) Hepatic
 decompensation-new onset ascites, encephalopathy, portal hypertensive bleeding or new
 hepatocellular carcinoma Death

 Should the subject have an injury or health problem that is due to taking part in this study,
 the subject or the subject's insurance will be responsible for the cost. The investigators do
 not expect any hospitalizations or complications requiring intervention.

 Treatment of clinical Herpes Zoster infection:

 All subjects who develop a clinical diagnosis of Herpes Zoster during the study will be
 treated with anti-virals if indicated and appropriate pain relief as needed. The subject or
 the subject's insurance will be responsible for the cost.

 Risks:

 There are risks associated with every drug study. The investigators do not suspect that the
 subjects will be placed at increased risk.

 Zostavax: Zostavax is considered very safe, but there are possible side effects,
 contraindications and warnings/precautions. The following are listed in the Zostavax Package
 Insert:

 Adverse Reactions The most frequent adverse reactions, reported in ≥1% of subjects vaccinated
 with Zostavax, were headache and injection-site reactions.

 Contraindications Hypersensitivity - Zostavax should not be administered to individuals with
 a history of anaphylactic/anaphylactoid reaction to gelatin, neomycin or any other component
 of the vaccine.

 Immunosuppression - Zostavax is a live, attenuated varicella-zoster vaccine and
 administration may result in disseminated disease in individuals who are immunosuppressed or
 immunodeficient. Zostavax should not be administered to immunosuppressed or immunodeficient
 individuals including those with a history of primary or acquired immunodeficiency states,
 leukemia, lymphoma or other malignant neoplasms affecting the bone marrow or lymphatic
 system, AIDS or other clinical manifestations of infection with human immunodeficiency
 viruses, and those on immunosuppressive therapy.

 Pregnancy - Zostavax should not be administered to pregnant women. It is not known whether
 Zostavax can cause fetal harm when administered to a pregnant woman or can affect
 reproduction capacity. However, naturally occurring VZV infection is known to sometimes cause
 fetal harm. Therefore, Zostavax should not be administered to pregnant women, and pregnancy
 should be avoided for 3 months following administration of Zostavax.

 Warnings and Precautions Hypersensitivity Reactions - Serious adverse reactions, including
 anaphylaxis, have occurred with Zostavax. Adequate treatment provisions, including
 epinephrine injection (1:1,000), should be available for immediate use should an
 anaphylactic/anaphylactoid reaction occur.

 Transmission of Vaccine Virus - Transmission of vaccine virus may occur between vaccinees and
 susceptible contacts.

 Concurrent Illness - Deferral should be considered in acute illness (for example, in the
 presence of fever) or in patients with active untreated tuberculosis.

 Limitations of Vaccine Effectiveness - Vaccination with Zostavax does not result in
 protection of all vaccine recipients. The duration of protection beyond 4 years after
 vaccination with Zostavax is unknown. The need for revaccination has not been defined.

 Zostavax is not indicated for nursing mothers. It is unknown if the vaccine is secreted in
 human milk, therefore, caution should be used in nursing women.

 Blood draw: There will be two blood draws 6 weeks apart which should be minimal risk. Risks
 include bruising, redness, or swelling at the site.

 Confidentiality: The identity of all subjects will be protected. Subjects will be assigned a
 unique identifier. Study related data will be kept in a database under password protection in
 a locked office. The Key will be stored separately in a locked file cabinet in a locked
 office. Data will be published and presented with complete anonymity to the subject.

 The study team will meet weekly to discuss the trial and evaluate adverse events and
 unanticipated events. All events will be monitored very closely. The study team will follow
 injection site reaction, development of Herpes Zoster, hepatic decompensation and any
 hospitalizations. A thorough history and physical will be done at screening and as needed to
 reduce the chance of adverse events.

 Consent process and documentation

 A member of the study team will obtain signed informed consent from each subject
 participating in the trial after an adequate explanation of the research purpose, personnel,
 procedures, risks and benefits, and the reiteration that research is voluntary. All of the
 subject's questions will be answered to his satisfaction. The subject will be given plenty of
 time to decide on participation and will not be made to feel obligated or coerced.

 Obtaining informed consent is a process, not just a document. If the risks change during the
 course of the project, it may be necessary to re-consent the subjects to ensure they are
 fully informed and still agree to participate.

 The informed consent document will be IRB approved. The signed informed consents will be kept
 for at least 3 years after the study ends.
Inclusion Criteria:

 -  Cirrhosis of any etiology diagnosed clinically by labs and imaging or by liver biopsy

 -  Male or Female age 50 to 70

 Exclusion Criteria:

 -  Active or history of Herpes Zoster

 -  Anaphylactic allergy to neomycin or gelatin

 -  Immunosuppressive medication use

 -  Antiviral medication use

 -  Known history of HIV

 -  Known immune deficiency disease

 -  Active on a liver transplant list

 -  Known malignancy other than non-melanomatous skin cancer within the past five years.

 -  History of vaccination with varicella or zoster vaccine

 -  Pregnant or lactating women

 -  Prisoners

 -  Post-transplant patient

 -  Acute illness