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

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'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. <= 25mg/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 study will
recruit 1,000 individuals age 50 years or older currently receiving anti-TNF therapy for RA
or other diseases. 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 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 patients using anti-TNF therapy, 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). Date of previous dose of
medication is required. 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 (SC) dose within 16 to 32 days depending on frequency
schedule (2 weeks + 2 days, or 4 weeks and 4 days), Golimumab Subcutaneous (SC) dose
within 32 days (4 weeks + 4 days), Golimumab Intravenous (IV) dose within 64 days (9
weeks + 1 day), Infliximab IV dose within last 64 days (9 weeks + 1 day)

**any form of biosimilar for the above listed anti-TNF medications is acceptable

- 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.