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

Rheumatoid Arthritis Clinical Trial

— VERVE  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02538757
• Other study ID #: VERVE-Pilot
• Status: Active, not recruiting
• Phase: Phase 2
• First received: August 18, 2015
• Last updated: July 25, 2017
• Start date: October 2013
• Est. completion date: August 2018

Study information

• Verified date: July 2017
• Source: University of Alabama at Birmingham
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The VaricElla zosteR VaccinE (VERVE) trial evaluates the safety and effectiveness of the herpes zoster (shingles) vaccine, Zostavax, in arthritis patients over 50 years old who are using anti-TNF therapy and who have not previously received the vaccine. This pilot study of 125 patients will serve as a backdrop for the larger study that is currently recruiting NCT02538341.

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 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.

Other known NCT identifiers

• NCT01967316

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 125
• Est. completion date: August 2018
• Est. primary completion date: February 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Ankylosing Spondylitis
• Arthritis
• Arthritis, Psoriatic
• Arthritis, Rheumatoid
• Crohn Disease
• Crohn's Disease
• Enteropathic Arthritis
• Inflammatory Arthritis
• Psoriasis
• Psoriatic Arthritis
• Rheumatoid Arthritis
• Spondylitis
• Spondylitis, Ankylosing

Intervention

Biological:
• Herpes Zoster Vaccine

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
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
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

External Links

•   Link to currently recruiting VERVE parent study, given that this pilot study is now ended