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

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

The VaricElla zosteR VaccinE (VERVE) trial evaluates the safety and effectiveness of the Herpes zoster (HZ) vaccine for shingles, Zostavax, in patients over 50 years old with arthritis and other diseases who are using anti-tumor necrosis factor (TNF) therapy and who have not previously received the vaccine.

Study Overview

• Status: Completed
• Conditions: Arthritis; Rheumatoid Arthritis; Psoriasis; Crohn's Disease; Inflammatory Arthritis; Psoriatic Arthritis; Ankylosing Spondylitis; Enteropathic Arthritis
• Intervention / Treatment: Drug: Placebo; Biological: Herpes Zoster (HZ) Vaccine

Detailed 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 herpes zoster (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 herpes zoster (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 (HZ) in rheumatoid arthritis patients is approximately double in the general population. This increased risk should make prevention of zoster and vaccination exceedingly important for rheumatoid arthritis patients. In fact, because of a higher overall absolute risk for herpes zoster (HZ) in rheumatoid arthritis, the vaccine yields a comparable or even greater absolute risk reduction to reduce the risk of shingles and post-herpetic neuralgia in a rheumatoid arthritis population as it does in the general population. However, the use of the herpes zoster (HZ) in rheumatoid arthritis, 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 herpes zoster (HZ) vaccine for all individuals age 60 or older, with the vaccine more recently gaining Federal Drug Administration (FDA) -approval for administration to persons age 50 and older. While a large number of rheumatoid arthritis 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 Advisory Committee on Immunization Practices (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 rheumatoid arthritis patients receiving biologic therapies with this vaccine may in fact be safe. Moreover, and similarly with little or no evidence, the Advisory Committee on Immunization Practices (ACIP) considers the vaccine safe and acceptable for patients using methotrexate at doses commonly used to treat rheumatoid arthritis (e.g. <= 25mg/week) and for patients using glucocorticoids at prednisone-equivalent doses of ≤ 20 mg/day.

In light of 1) a substantial elevated herpes zoster (HZ) risk among rheumatoid arthritis patients; 2) national data showing most rheumatoid arthritis patients are not vaccinated for herpes zoster (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 (HZ) vaccine. This study will recruit 1,000 individuals age 50 years or older currently receiving anti-tumor necrosis factor (TNF) therapy for rheumatoid arthritis or other diseases. Within a relevant 6-week safety window, the investigators will collect serious adverse events (satisfying a regulatory definition of a Serious Adverse Event) including non-serious events of vaccine-strain varicella-like infection or herpes zoster (HZ). 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 rheumatoid arthritis management by demonstrating the clinical safety and immunogenicity of the live zoster vaccine among current anti-tumor necrosis factor (TNF) users. Rheumatologists and other providers will be able to improve the care, outcomes, and quality of life for patients using anti-tumor necrosis factor (TNF) therapy, substantially decreasing the morbidity of herpes zoster and its complications over a lifetime.

• Study Type: Interventional
• Enrollment (Actual): 617
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
    • Birmingham, Alabama, United States, 35205
      • Total Skin and Beauty Dermatology Center, PC
    • Birmingham, Alabama, United States, 35205
      • Rheumatology Associates, Pc
    • Huntsville, Alabama, United States, 35801
      • Rheumatology Associates of North Alabama, PC
    • Tuscaloosa, Alabama, United States, 35406
      • Clinical and Translational Research Center of Alabama, PC
  • Arizona
    • Peoria, Arizona, United States, 85381
      • SunValley Arthritis Center, Ltd
  • California
    • Los Angeles, California, United States, 90015
      • Arthritis Association of Southern California
    • Los Angeles, California, United States, 90095
      • The Regents of the University of California Los Angeles
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Rheumatology Consultants of Delaware dba Delaware Arthritis
  • Florida
    • Miami, Florida, United States, 33175
      • Coral Research Clinic Corp
    • Miami, Florida, United States, 33157
      • Center for Arthritis and Rheumatic Diseases
    • Palm Harbor, Florida, United States, 34684
      • Arthritis Research of Florida, INC
    • Sarasota, Florida, United States, 34239
      • Sarasota Arthritis Research Center
    • Tamarac, Florida, United States, 33321
      • West Broward Rheumatology Associates, Inc
  • Georgia
    • Lawrenceville, Georgia, United States, 30046
      • North Georgia Rheumatology Group
  • Kansas
    • Wichita, Kansas, United States, 67214
      • Arthritis Research Center Foundation, NDB
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Ochsner Clinic Baton Rouge
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation, New Orleans
    • Shreveport, Louisiana, United States, 71101
      • Rheumatology & Osteoporosis Specialists
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
  • Michigan
    • East Lansing, Michigan, United States, 48823
      • Pine Hollow Partners
  • Minnesota
    • Eagan, Minnesota, United States, 55121
      • St. Paul Rheumatology
  • Nebraska
    • Omaha, Nebraska, United States, 68106
      • University of Nebraska Medical Center
  • New York
    • Albany, New York, United States, 12293
      • The Center For Rheumatology, Llp
    • Cooperstown, New York, United States, 13326
      • Mary Imogene Bassett Hospital, Bassett Research Institute
  • Ohio
    • Columbus, Ohio, United States, 43203
      • The Ohio State University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Center For Clinical Research
  • South Carolina
    • Myrtle Beach, South Carolina, United States, 29572
      • Carolina Health Specialists
  • Tennessee
    • Hixson, Tennessee, United States, 37343
      • Arthritis Associates, PLLC
    • Jackson, Tennessee, United States, 38305
      • West Tennessee Research Institute
  • Texas
    • Mesquite, Texas, United States, 75150
      • SouthWest Rheumatology Research, LLC
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
  • West Virginia
    • South Charleston, West Virginia, United States, 25309
      • West Virginia Research Institute, PLLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Must be 50 years of age or older

• Must be currently treated with an anti-tumor necrosis factor (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-tumor necrosis factor (TNF) medications is acceptable

• Diagnosis of rheumatoid arthritis or another inflammatory arthritis (Phase 1A); or other inflammatory condition (e.g. psoriasis) requiring use of anti-tumor necrosis factor (TNF) therapy (Phase 1B and II)
• Phase I subjects must test positive for varicella-zoster virus (VZV) antibody 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 United States.
• 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 Disease-modifying antirheumatic drugs (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 varicella-zoster virus (VZV) antibody immunoglobulin G (IgG) 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 1A patients)
• Any known contraindication to Zostavax® vaccine, including allergy or sensitivity to gelatin or any other vaccine component
• Known human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Zostavax (Zoster Vaccine Live); Zostavax (zoster vaccine live) is used to prevent herpes zoster (HZ) virus (shingles) in people age 50 and older. Patients randomized to this arm will receive active herpes zoster (HZ) vaccine. It is administered as a single 0.65 mL dose subcutaneously in the deltoid region of the upper arm.	Biological: Herpes Zoster (HZ) Vaccine; Other Names: Zostavax
Placebo Comparator: Placebo Normal Saline; Saline injection: patients randomized to this arm will receive a single 0.65 mL dose subcutaneously in the deltoid region of the upper arm.	Drug: Placebo; Other Names: Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GMFR (Geometric Mean Fold Rise ) in Varicella Zoster Virus (VZV) Glycoprotein Enzyme-linked Immunosorbent Assay (gpELISA) Immunoglobulin G (IgG) Levels From Baseline at 6 Weeks	Study protocol defined measure for immunogenicity samples.	6 weeks post vaccination
GMFR (Geometric Mean Fold Rise ) in Varicella Zoster Virus (VZV) Enzyme-linked Immune Absorbent Spot (ELISpot) Interferon Gamma (IFNg) Levels From Baseline at 6 Weeks	Study protocol defined measure for immunogenicity samples.	6 weeks post vaccination

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GMFR (Geometric Mean Fold Rise ) in Varicella Zoster Virus (VZV) Glycoprotein Enzyme-linked Immunosorbent Assay (gpELISA) Immunoglobulin G (IgG) Levels From Baseline at 1 Year	Study defined measure from labs. GMFR (Geometric Mean Fold Rise ) in varicella zoster virus (VZV) glycoprotein enzyme-linked immunosorbent assay (gpELISA) immunoglobulin G (IgG) levels	Baseline to 1 year
GMFR (Geometric Mean Fold Rise ) in Varicella Zoster Virus (VZV) Enzyme-linked Immune Absorbent Spot (ELISpot) Interferon Gamma (IFNg) Levels From Baseline at 1 Year	Study defined measures from labs. GMFR (Geometric Mean Fold Rise ) in Varicella Zoster Virus (VZV) enzyme-linked immune absorbent spot (ELISpot) interferon gamma (IFNg)	Baseline to 1 year
Number of Samples With Confirmed Varicella	Evaluated all serious adverse events (SAEs) AND non-serious varicella zoster virus (VZV) events	"Placebo Normal Saline Arm/Group was assessed up to 6 months and the "Zoster Vaccine Live (Zostavax)" Arm/Group was assessed up to 1 year
Vaccine Tolerability Within 42 Days Following Vaccination.	Patient self report data in the form of a diary to include injection site reactions; symptoms of swelling, redness or tenderness. Diary was completed from study injection administration up to 6 week visit	42 days post vaccination
Evaluate Rheumatoid Arthritis Disease Activity Using the Clinical Disease Activity Index (CDAI)	Rheumatoid arthritis disease activity will be measured using the clinical disease activity index (CDAI). Clinical disease activity index (CDAI) is a measure of rheumatoid arthritis disease activity and is scored on a scale ranging from 0-76, with lower numbers indicated better control of disease. Values <=10 are consistent with low disease activity or remission.	42 days post vaccination

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Oregon Health and Science University
• Investigators: Principal Investigator: Jeffrey R Curtis, MD, MS, MPH, University of Alabama at Birmingham

Publications and helpful links

General Publications

• Curtis JR, Cofield SS, Bridges SL Jr, Bassler J, Deodhar A, Ford TL, Huffstutter J, Jankeel A, Kivitz A, Kamal S, Lindsey S, Messaoudi I, Mendoza N, Michaud K, Mikuls TR, Ridley D, Shergy W, Siegel SAR, Winthrop KL. The Safety and Immunologic Effectiveness of the Live Varicella-Zoster Vaccine in Patients Receiving Tumor Necrosis Factor Inhibitor Therapy : A Randomized Controlled Trial. Ann Intern Med. 2021 Nov;174(11):1510-1518. doi: 10.7326/M20-6928. Epub 2021 Sep 28.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Actual): December 1, 2019
• Study Completion (Actual): December 1, 2020

Study Registration Dates

• First Submitted: August 18, 2015
• First Submitted That Met QC Criteria: August 30, 2015
• First Posted (Estimate): September 2, 2015

Study Record Updates

• Last Update Posted (Actual): November 23, 2021
• Last Update Submitted That Met QC Criteria: October 23, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Skin Diseases; Infections; Gastrointestinal Diseases; Joint Diseases; Musculoskeletal Diseases; Gastroenteritis; Intestinal Diseases; Skin Diseases, Papulosquamous; Spinal Diseases; Bone Diseases; Inflammatory Bowel Diseases; Spondylarthropathies; Spondylarthritis; Bone Diseases, Infectious; Ankylosis; Arthritis; Psoriasis; Crohn Disease; Arthritis, Psoriatic; Spondylitis; Spondylitis, Ankylosing
• Other Study ID Numbers: VERVE-UM1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL