Safety and Effectiveness Study of the Live Zoster Vaccine in Anti-TNF Users

Rheumatoid Arthritis Clinical Trial

— VERVE  

Official title:

A Pilot Study of the Safety and Effectiveness of the Live Zoster Vaccine in Anti-TNF Users

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01967316
• Other study ID #: VERVE
• Status: Recruiting
• Phase: Phase 2
• First received: July 9, 2013
• Last updated: April 6, 2016
• Start date: May 2014
• Est. completion date: June 2016

Study information

• Verified date: April 2016
• Source: University of Alabama at Birmingham
• Contact: Randall Parks, MBA
• Phone: 205-934-7727
• Email: rand1951[@]uab.edu
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to test the hypothesis that the vaccination with Zostavax is non-inferior to placebo injection in a population of patients that are currently over the age of 50 and on an anti-TNF.

Description:

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 that in the general population. This increased risk should make prevention of zoster and therefore 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 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 disseminated varicella-like infection from the vaccine virus strain. However, the investigators hypothesize that this vaccine can safely be given in this setting, as there are no published data to suggest that these safety concerns are warranted, and a growing body of observational data suggest 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 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 being addressed, clinical trial methodological innovations proposed 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 125
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 50 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis of RA (ACR 1987 criteria) or another inflammatory arthritis

• Must be 50 years of age or older

• Must be currently treated with an anti-TNF therapy at the time of vaccination. Specifically, most recent weekly etanercept dose must have occurred within 7 days, most recent adalimumab dose must have occurred within 14 days, most recent certolizumab dose must have occurred within 14 days, most recent golimumab dose must have occurred within 30 days, and most recent infliximab infusion must have occurred within 56 days.

• Must be receiving an anti-TNF therapy for an inflammatory arthritis (i.e. rheumatoid arthritis or a spondyloarthropathy such as psoriatic arthritis, ankylosing spondylitis or enteropathic arthritis). Based upon the age requirement and RA prevalence, we expect the vast majority of patients will have rheumatoid arthritis.

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

• The first 250 patients recruited to Phase I 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.

• The first 100 patients recruited to phase I must not have received any oral or systemic glucocorticoids within 30 days prior to vaccination. Intra-articular glucocorticoid injections 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.

Exclusion Criteria:

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

• Glucocorticoids at a prednisone-equivalent daily dose > 10mg/day

• 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, or famciclovir

• 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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Biological:
• Herpes Zoster Vaccine
0.65 mL dose injection at baseline visit.

Drug:
• Placebo

Locations

Country	Name	City	State
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Oregon Health Science University	Portland	Oregon

Sponsors (2)

Lead Sponsor	Collaborator
University of Alabama at Birmingham	Oregon Health and Science University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Immunogenicity measured at 6 weeks.	The primary outcome will be a two-group t-test between the active and placebo group, comparing the difference in the frequency of VZV-specific T cell response using ELISPOT from baseline to week 6.	6 weeks post vaccination	No
Secondary	The clinical effectiveness of the HZ vaccine in reducing longer-term HZ risk.	Incident HZ cases occurring up to 2 years following vaccination and beyond will be ascertained among enrollees in Medicare and/or a large commercial health plan using a novel linkage to administrative health plan data. We will examine longer-term reduction in risk for herpes zoster and the potential for decreased vaccine effectiveness over time to prevent HZ, which might suggest waning immunity and the need for re-vaccination. This outcome will be ascertained using administrative claims data among the majority of VERVE participants who are linkable to the health plan data sources available to the trial.	2 years post vaccination	No
Secondary	Vaccine safety of all serious adverse events (SAEs) AND non-serious vaccine-strain VZV events within 42 days of vaccination	Serious adverse events of interest will include all serious adverse events that satisfy the FDA-accepted definition of SAEs (results in death, life threatening, results in or prolongs hospitalization, etc.). The hypothesis to be tested by the trial is that vaccination with Zostavax® is non-inferior to placebo injection in the cumulative incidence of the composite safety outcome occurring within 42 days after vaccination. We will also examine vaccine tolerability including injection site reactions and flares in RA disease activity within 6 weeks following vaccination. RA disease activity will be measured using the clinical disease activity index (CDAI) and the Rapid Assessment of Patient Data (RAPID3)	42 days post vaccination	Yes
Secondary	Additional measures of immunogenicity, measured at 6 week	Difference between intervention and placebo for VZV glycoprotein-specific antibody titers.	42 days post vaccination	No