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

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ClinicalTrials.gov Identifier: NCT02538341
Recruitment Status : Recruiting
First Posted : September 2, 2015
Last Update Posted : July 10, 2018
Sponsor:
Collaborator:
Oregon Health and Science University
Information provided by (Responsible Party):
Jeff Curtis, MD, University of Alabama at Birmingham

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

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Inflammatory Arthritis Arthritis Psoriatic Arthritis Psoriasis Ankylosing Spondylitis Enteropathic Arthritis Crohn's Disease Biological: Herpes Zoster Vaccine Drug: Placebo Phase 2

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 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Safety and Effectiveness of Live Zoster Vaccine in Anti-TNF Users (VERVE Trial)
Study Start Date : May 2016
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : September 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Shingles

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




Primary Outcome Measures :
  1. Immunogenicity measured at 6 weeks. [ Time Frame: 6 weeks post vaccination ]
    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 the Enzyme-Linked ImmunoSpot (ELISPOT) assay from baseline to week 6.


Secondary Outcome Measures :
  1. The clinical effectiveness of the HZ vaccine in reducing longer-term HZ risk [ Time Frame: 2 years post vaccination ]
    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. The investigators 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. Estimate vaccine safety [ Time Frame: 42 days post vaccination ]

    Evaluate 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, and any Herpes Zoster event).

    Adverse events (non-serious) will include rashes, blisters, fever of greater than 101, sickness/illness. Also, any redness, swelling, tenderness of the injection site or any other body part.


  3. Vaccine tolerability [ Time Frame: 42 days post vaccination ]
    Vaccine tolerability will be measured by injection site reactions and RA flares within 42 days following vaccination.

  4. Evaluate RA disease activity [ Time Frame: 42 days post vaccination ]
    RA Disease activity will be measured using the clinical disease activity index (CDAI) and the Rapid Assessment of Patient Data (RAPID3).



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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02538341


Contacts
Contact: Mary Melton (205) 975-2287 melkins@uabmc.edu

  Show 34 Study Locations
Sponsors and Collaborators
University of Alabama at Birmingham
Oregon Health and Science University
Investigators
Principal Investigator: Jeffrey R Curtis, MD, MS, MPH University of Alabama at Birmingham

Responsible Party: Jeff Curtis, MD, Principal Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT02538341     History of Changes
Obsolete Identifiers: NCT01967316, NCT02538757
Other Study ID Numbers: VERVE-UM1
First Posted: September 2, 2015    Key Record Dates
Last Update Posted: July 10, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Psoriasis
Crohn Disease
Spondylitis
Spondylitis, Ankylosing
Arthritis, Psoriatic
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Skin Diseases, Papulosquamous
Skin Diseases
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Bone Diseases, Infectious
Infection
Bone Diseases
Spinal Diseases
Spondylarthropathies
Spondylarthritis
Ankylosis
Vaccines
Immunologic Factors
Physiological Effects of Drugs