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The Immunogenicity and Safety of Zostavax® in Rheumatoid Arthritis Patients Using Abatacept (BMS-188667)

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ClinicalTrials.gov Identifier: NCT03604406
Recruitment Status : Recruiting
First Posted : July 27, 2018
Last Update Posted : May 3, 2019
Sponsor:
Collaborators:
University of Alabama at Birmingham
Bristol-Myers Squibb
Information provided by (Responsible Party):
Kevin Winthrop, Oregon Health and Science University

Brief Summary:
This investigator-initiated study will serve as a sub-study for the American College of Rheumatology-sponsored VERVE protocol currently funded by the NIH. This double-blinded multicenter randomized pragmatic trial is designed to determine whether Zostavax is safe and effective in patients with rheumatoid arthritis (RA) currently using anti-tumor necrosis factor (TNF) therapies. Inclusion/exclusion criteria for this sub-study mirror that of the parent VERVE trial with the exception of abatacept therapy being allowed. Preliminary data from the VERVE parent protocol enrolling patients using anti-TNF therapy is encouraging in that few patients experienced adverse events (56 adverse events in 50 participants, out of 140 participants in total) and that 96.2% of these adverse events were considered either mild or moderate. Importantly, there have been no instances of vaccine dissemination or zoster events to date.

Condition or disease Intervention/treatment Phase
Herpes Zoster Inflammatory Disease Rheumatoid Arthritis Biological: Varicella Zoster Vaccine Other: Placebo Injection Phase 2

Detailed Description:

Recently, a live-attenuated vaccine (Zostavax®, Merck) to prevent herpes zoster (HZ) has been developed and approved for use among individuals age 50 years or older, regardless of previous HZ or varicella history. In a pivotal study of 38,456 older adults led by Dr. Michael Oxman (a co-investigator in the parent VERVE trial and this immunogenicity pilot sub-study), the vaccine reduced the incidence of HZ and postherpetic neuralgia (PHN) by > 50%.

Guidelines from the American Council on Immunization Practices (ACIP), based largely on expert opinion (given the absence of data), recommend that patients who use methotrexate or low to moderate doses of corticosteroids (up to 20mg/day prednisone) can receive this vaccination safely. However, theoretical concerns regarding the safety of live vaccine use in patients using biologic therapies have resulted in an ACIP recommendation that the vaccine is contraindicated in patients receiving such medications. Similarly, given a lack of data, the American College of Rheumatology (ACR) endorsed this contraindication in the updated ACR 2012 recommendations for biologic and non-biologic disease modifying anti-rheumatic drug (DMARD) use in RA patients (led by members of the project team for this present application).

Currently it is unknown if RA patients using biologics can safely receive this vaccine. Despite the demonstrated efficacy and safety of the zoster vaccine observed in non-RA patients, there are no prospective data critically examining the efficacy or safety of HZ vaccination in RA patients. The zoster vaccine was not given to immunosuppressed patients in the large Shingles Prevention Study (SPS); RA patients and others receiving biologics and immunosuppressive agents including glucocorticoids and DMARDs were excluded. However, this trial did show safety of the vaccine even for very elderly individuals including those older than 70 years of age and with little evidence of remaining VZV-specific cell mediated immunity (CMI). Moreover, live varicella vaccine has been safely given to children with HIV infection. Recently, the investigators used the administrative databases of a national U.S. Healthcare organization (Aetna) to conduct an observational study to examining Zostavax use in patients with RA and other rheumatic diseases (e.g. spondyloarthropathies). Among a total of 19,326 RA patients older than age 50, only 206 (1%) received zoster vaccine, suggesting that clinicians may be uncomfortable using the vaccine in RA patients. Additionally, approximately 60 vaccinated patients were using anti-TNF therapies within one month of vaccination, and no cases of HZ were reported during this time frame. Some studies suggest an elevated risk of HZ in RA patients using anti-TNF therapies, although HZ cases reported within these cohorts of anti-TNF users do not show increased dissemination or complications, suggesting that anti-TNF therapy might not necessarily increase the likelihood of VZV dissemination in such patients. Theoretically, however, with downregulation of interferon-gamma pathways associated with TNF blockade, an increase risk of HZ might be expected in such patients. Lastly, limited head-to-head data collected to date suggests abatacept might carry less risk of HZ and other opportunistic infections than does anti-TNF therapy. Given the widespread use of anti-TNF and other biologic therapies like abatacept, many RA patients and rheumatologists are unwilling to stop biologic therapy in order to receive Zostavax. This represents a missed opportunity with regard to HZ prevention. Clearly, given the high risk of HZ in the RA population, it would be highly beneficial to prospectively evaluate the safety and efficacy of this vaccine in patients using biologic therapy.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: The Immunogenicity and Safety of Zostavax® in Rheumatoid Arthritis Patients Using Abatacept
Actual Study Start Date : May 8, 2014
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : June 2023


Arm Intervention/treatment
Experimental: Varicella Zoster Vaccine
Live zoster vaccine injection will be administered as a single 0.65-mL dose subcutaneously in the deltoid region of the upper arm at the baseline visit
Biological: Varicella Zoster Vaccine
live-attenuated vaccine to prevent herpes zoster
Other Name: Zostavax

Placebo Comparator: Placebo Injection
Saline injection will be administered as a single 0.65-mL dose subcutaneously in the deltoid region of the upper arm at the baseline visit
Other: Placebo Injection
Saline solution injection




Primary Outcome Measures :
  1. Change in ELISPOT response from baseline to week 6, and one year post vaccination [ Time Frame: 1) Baseline visit prior to vaccination; 2) 6 weeks post-vaccination; 3) 1 year post-vaccination ]

    Surrogate measures of vaccine efficacy will be performed on all patients using samples collected at baseline prior to vaccination, and subsequently at 6 weeks, and one year post vaccination. These measures will include:

    a. Frequency of VZV-specific T cells as measured by interferon-gamma ELISPOT assay.

    Changes in these outcome measures will be evaluated using geometric means and percentage increases in geometric means of (a) VZV-specific reactive lymphocytes.


  2. Change in IgG titer from baseline to week 6, and one year post vaccination [ Time Frame: 1) Baseline visit prior to vaccination; 2) 6 weeks post-vaccination; 3) 1 year post-vaccination ]

    Surrogate measures of vaccine efficacy will be performed on all patients using samples collected at baseline prior to vaccination, and subsequently at 6 weeks, and one year post vaccination. These measures will include:

    b. VZVgp-specific IgG titer as measured by ELISA

    Changes in these outcome measures will be evaluated using geometric means and percentage increases in geometric means of (b) VZV antibody titers in vaccine recipients as compared to placebo, as well as relative to baseline measures prior to vaccination.



Secondary Outcome Measures :
  1. Development of Varicella Zoster Virus [ Time Frame: Within 42 days of vaccination ]
    The primary adverse event of interest is development of varicella (ie zoster rash or disseminated complications of varicella) within 42 days of vaccination or any serious adverse event as defined according to standard regulatory definitions.



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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:

  • Currently treated with abatacept therapy at the time of enrollment.
  • Eligible women must be post-menopausal (> 1 year since last menstrual period) or have a surgical history of bilateral oophorectomy or hysterectomy.
  • History of prior chicken pox (positive varicella IgG serology can be used to document prior exposure)

Exclusion Criteria:

  • Prior zostavax receipt
  • Active contraindications to vaccination including allergy or sensitivity to gelatin or any other vaccine component
  • Acute illness or infection
  • HIV/AIDS
  • Current systemic corticosteroid use (including any oral or parenteral use in the previous 28 days)
  • Dose of DMARDs not stable for > 30 days
  • Concomitant TNF antagonist use
  • Receiving radiation or chemotherapy for cancer treatment
  • Current leukemia, lymphoma, or other cancer affecting bone marrow or lymphatic system cellular immunodeficiency
  • Current use of anti-viral medications against the herpes virus family
  • Received any live virus vaccine within 28 days prior to study entry
  • Received any inactivated vaccine within 7 days prior to study entry
  • Known household contacts who may be susceptible to a live virus vaccine (e.g. pregnant women).

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): NCT03604406


Contacts
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Contact: Amanda Brunton, MPH 503-494-6327 brunton@ohsu.edu

Locations
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United States, Alabama
Rheumatology Associates of North Alabama Recruiting
Huntsville, Alabama, United States, 35801
Contact: Theresa Causey    256-704-7098    tcausey@rana-hsv.org   
United States, Minnesota
St. Paul Rheumatology Not yet recruiting
Eagan, Minnesota, United States, 55121
Contact: Nathan Cameron    651-361-8659    nathan@sprdrem.com   
United States, Oregon
Oregon Health & Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Amanda Brunton, MPH    503-494-6327    brunton@ohsu.edu   
Principal Investigator: Kevin L Winthrop, MD, MPH         
United States, Tennessee
Arthritis Associates Not yet recruiting
Hixson, Tennessee, United States, 37343
Contact: Joseph Huffstutter, MD    423-886-9641    jhuff@arthchatt.com   
Sponsors and Collaborators
Kevin Winthrop
University of Alabama at Birmingham
Bristol-Myers Squibb

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Responsible Party: Kevin Winthrop, Associate Professor, Oregon Health and Science University
ClinicalTrials.gov Identifier: NCT03604406     History of Changes
Other Study ID Numbers: 10433
First Posted: July 27, 2018    Key Record Dates
Last Update Posted: May 3, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Kevin Winthrop, Oregon Health and Science University:
Shingles
abatacept
Varicella Zoster Vaccine

Additional relevant MeSH terms:
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Herpes Zoster
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Varicella Zoster Virus Infection
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Vaccines
Abatacept
Immunologic Factors
Physiological Effects of Drugs
Immunosuppressive Agents
Antirheumatic Agents