Placebo Controlled Evaluation of the Cell Mediated Immune Response of Cirrhotic Subjects to Zostavax™
Condition: Herpes Zoster; Fibrosis
MeSH terms: Herpes Zoster
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Zostavax; Placebo
Intervention type(s): Biological; Other
Intervention description(s): Vaccination with one dose of Zostavax per Zostavax package insert; Injection of 0.65 mL of sterile normal saline
Other intervention name(s): Zoster Vaccine Live
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention