Safety and Effectiveness Study of the Live Zoster Vaccine in Anti-Tumor Necrosis Factor (TNF) Users (VERVE)

Herpes zoster (HZ), also known as "shingles", is caused by reactivation and multiplication
of the ubiquitous varicella zoster virus (VZV) that remains latent in everyone's sensory
neurons following varicella, or "chickenpox". Among individuals who live to age 85, the
lifetime risk for HZ is 50%, and more than one in five individuals affected by zoster
develop post-herpetic neuralgia, resulting in chronic pain. Other serious complications
include encephalitis, permanent vision loss, or more rarely, dissemination and death.
Fortunately, a live attenuated vaccine is available and can reduce HZ risk by up to 70%. For
patients with rheumatoid arthritis (RA), this vaccine has great potential to provide
improved quality of life by reducing the incidence and complications associated with zoster.
Due to the underlying disease and/or treatments (e.g. steroids) for rheumatoid arthritis
(RA), the risk of herpes zoster in RA patients is approximately double in the general
population. This increased risk should make prevention of zoster and vaccination exceedingly
important for RA patients. In fact, because of a higher overall absolute risk for zoster in
RA, the vaccine yields a comparable or even greater absolute risk reduction to reduce the
risk of shingles and post-herpetic neuralgia in an RA population as it does in the general
population. However, the use of the zoster vaccine in RA patients is very low (< 5%), and
less frequently used than for the general population.

National guidelines from the Centers for Disease Control and Prevention's (CDC) Advisory
Committee on Immunization Practices (ACIP) recommend a single dose of the zoster vaccine for
all individuals age 60 or older, with the vaccine more recently gaining FDA-approval for
administration to persons age 50 and older. While a large number of RA patients would
otherwise be recommended to receive this vaccine on the basis of age, theoretical safety
concerns related to vaccination likely explain the very low vaccination rates observed.
Currently, the Federal Drug Administration (FDA), the ACIP, and the American College of
Rheumatology (ACR) consider the live zoster vaccine contraindicated in patients receiving
immunosuppressive medications, such as biologic therapies. Such contraindication stems from
the theoretical safety concern that these individuals could develop a varicella-like
infection from the vaccine virus strain. However, investigators hypothesize that this
vaccine can safely be given in this setting, as no published data is available to suggest
that these safety concerns are warranted. A growing body of observational data suggests that
vaccinating RA patients receiving biologic therapies with this vaccine may in fact be safe.
Moreover, and similarly with little or no evidence, the ACIP considers the vaccine safe and
acceptable for patients using methotrexate at doses commonly used to treat RA (e.g. <= 25
mg/week) and for patients using glucocorticoids at prednisone-equivalent doses of ≤ 20
mg/day.

In light of 1) a substantial elevated HZ risk among RA patients; 2) national data showing
most RA patients are not vaccinated for HZ; and 3) the high effectiveness of this vaccine in
the general population, the investigators propose to conduct the Varicella zostER VaccinE
(VERVE) trial, a randomized, double-blind, placebo-controlled study to evaluate the safety,
tolerability, and long-term effectiveness of the live herpes zoster vaccine. This pilot
study will recruit the first 125 patients of the needed 1,000 individuals age 50 years or
older currently receiving anti-TNF therapy for RA or other inflammatory arthritis. Within a
relevant 6-week safety window, the investigators will collect serious adverse events
(satisfying a regulatory definition of a SAE) including non-serious events of vaccine-strain
varicella-like infection or herpes zoster. Beyond the key public health importance of the
clinical question addressed, clinical trial methodological innovations anticipated for this
unique large pragmatic trial. Additionally, the investigators will study vaccine
tolerability and long-term effectiveness through a linkage to health plan data to allow for
cost-effective follow-up while minimizing participant and study-site burden. Results from
this pilot study will facilitate the parent trial and change RA management by demonstrating
the clinical safety and immunogenicity of the live zoster vaccine among current anti-TNF
users. Rheumatologists and other providers will be able to improve the care, outcomes, and
quality of life for RA patients, substantially decreasing the morbidity of herpes zoster and
its complications over a lifetime.

Inclusion Criteria:

- Must be 50 years of age or older

- Must be currently treated with an anti-TNF therapy at the time of study drug
administration, allowing for small deviations in dosing frequency and logistic
feasibility (e.g. study visits to occur on a week day). Specifically, meets one of
the following: Etanercept dose within 9 days (1 week + 2 days); Adalimumab dose
within 16 days (2 weeks + 2 days); Certolizumab subcutaneous (q2 weeks) dose within
16 days (2 weeks + 2 days); Certolizumab subcutaneous (q4 weeks) dose within 32 days
(4 weeks + 4 days); Golimumab subcutaneous (q4 weeks) dose within 32 days (4 weeks +
4 days); Golimumab IV (q8 weeks) dose within 64 days (9 weeks + 1 day); Infliximab IV
(q8 weeks) dose within last 64 days (9 weeks + 1 day); (Date of previous dose of
medication is required)

- Diagnosis of RA or another inflammatory arthritis (Phase Ia); or RA, another
inflammatory arthritis, or other inflammatory condition (e.g. psoriasis) requiring
use of anti-TNF therapy (Phase Ib and II)

- Phase I subjects must test positive for VZV immunoglobulin G (IgG)

- Subjects should have a self-reported history of prior varicella infection (i.e.
chicken pox) or long-term residence (>30 years) in the continental US.

- Phase Ia subjects must not have received any oral or systemic glucocorticoids within
30 days prior to vaccination. Intra-articular glucocorticoid injections and inhaled
glucocorticoids within the previous 30 days are acceptable.

- Subjects should be on stable doses of all biologic and non-biologic DMARDs for a
minimum of 30 days prior to vaccination.

- Eligible women must be post-menopausal (> 1 year since last menstrual period) or have
a surgical history of bilateral oophorectomy or hysterectomy.

- Subjects should be ambulatory, community dwelling and capable of giving informed
consent.

Exclusion Criteria:

- Documented VZV negative result

- Prior use of the zoster vaccine (Zostavax®, Merck)

- Glucocorticoids at a prednisone-equivalent daily dose > 10mg/day (for Phase 1b and
Phase II participants; all systemic glucocorticoid use is prohibited for Phase Ia
patients)

- Any known contraindication to Zostavax® vaccine, including allergy or sensitivity to
gelatin or any other vaccine component

- Known HIV/AIDS

- Currently receiving radiation or chemotherapy for any type of malignancy

- Any current use (within the last 30 days) of acyclovir, valacyclovir, famciclovir, or
foscarnet

- Receipt of any other immunizations within one month before study vaccination (2 weeks
in the case of inactivated influenza vaccines or other non-replicating immunization
products [e.g., diphtheria-tetanus (dT), pneumococcal vaccine, hepatitis A vaccine,
hepatitis B vaccine]), or scheduled within 6 weeks after recruitment.

- Active infection or inter-current illness (e.g., urinary tract infection, influenza)

- Participated in an investigational study within 1 month prior to study entry

- Active drug or alcohol use, dependence, or any other reason that, in the opinion of
the site investigator, would interfere with the study

- Significant underlying illness that would be expected to prevent completion of the
study (e.g., life-threatening disease likely to limit survival to less than 3 years)

- Any other reason that, in the opinion of the site investigator, would interfere with
required study related evaluations (e.g. uncontrolled comorbidity, life expectancy <
1 year)

- Patients who have household contact with varicella-susceptible pregnant women or
severely immunosuppressed individuals without history of primary varicella.