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

NCT ID: NCT02538341

Last Updated: 2021-11-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 617 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-05-31
• Study Completion Date: 2020-12-31

Brief Summary

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.

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Herpes Zoster (HZ) Vaccine

Intervention Type: BIOLOGICAL

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Interventions

Herpes Zoster (HZ) Vaccine

Intervention Type: BIOLOGICAL

Placebo

Intervention Type: DRUG

Other Intervention Names

Zostavax; Normal Saline

Eligibility Criteria

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.

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Oregon Health and Science University

OTHER

Sponsor Role: collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Jeff Curtis, MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jeffrey R Curtis, MD, MS, MPH

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Locations

Rheumatology Associates, PC

Birmingham, Alabama, United States

Total Skin and Beauty Dermatology Center, PC

Birmingham, Alabama, United States

University of Alabama at Birmingham

Birmingham, Alabama, United States

Rheumatology Associates of North Alabama, PC

Huntsville, Alabama, United States

Clinical and Translational Research Center of Alabama, PC

Tuscaloosa, Alabama, United States

SunValley Arthritis Center, Ltd

Peoria, Arizona, United States

Arthritis Association of Southern California

Los Angeles, California, United States

The Regents of the University of California Los Angeles

Los Angeles, California, United States

Rheumatology Consultants of Delaware dba Delaware Arthritis

Lewes, Delaware, United States

Center for Arthritis and Rheumatic Diseases

Miami, Florida, United States

Coral Research Clinic Corp

Miami, Florida, United States

Arthritis Research of Florida, Inc

Palm Harbor, Florida, United States

Sarasota Arthritis Research Center

Sarasota, Florida, United States

West Broward Rheumatology Associates, Inc

Tamarac, Florida, United States

North Georgia Rheumatology Group

Lawrenceville, Georgia, United States

Arthritis Research Center Foundation, NDB

Wichita, Kansas, United States

Ochsner Clinic Baton Rouge

Baton Rouge, Louisiana, United States

Ochsner Clinic Foundation, New Orleans

New Orleans, Louisiana, United States

Rheumatology & Osteoporosis Specialists

Shreveport, Louisiana, United States

Boston Medical Center

Boston, Massachusetts, United States

Pine Hollow Partners

East Lansing, Michigan, United States

St. Paul Rheumatology

Eagan, Minnesota, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

The Center for Rheumatology, LLP

Albany, New York, United States

Mary Imogene Bassett Hospital, Bassett Research Institute

Cooperstown, New York, United States

The Ohio State University

Columbus, Ohio, United States

Oregon Health & Science University

Portland, Oregon, United States

Altoona Center for Clinical Research

Duncansville, Pennsylvania, United States

Carolina Health Specialists

Myrtle Beach, South Carolina, United States

Arthritis Associates, PLLC

Hixson, Tennessee, United States

West Tennessee Research Institute

Jackson, Tennessee, United States

Southwest Rheumatology Research, LLC

Mesquite, Texas, United States

University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States

West Virginia Research Institute, PLLC

South Charleston, West Virginia, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 34570596 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

VERVE-UM1

Identifier Type: -

Identifier Source: org_study_id

NCT01967316

Identifier Type: -

Identifier Source: nct_alias

NCT02538757

Identifier Type: -

Identifier Source: nct_alias