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

Primary Purpose

Herpes Zoster, Inflammatory Disease, Rheumatoid Arthritis

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Varicella Zoster Vaccine
Placebo Injection
Varicella Zoster Vaccine
Sponsored by
Kevin Winthrop
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Herpes Zoster focused on measuring Shingles, abatacept, Varicella Zoster Vaccine

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria include:

  • be >= 50 years of age or older (for the Zostavax® sub-study only)
  • be >= 18 years of age or older (for the Shingrix® sub-study only)
  • be 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 (for the Zostavax® sub-study only).
  • Female participants of childbearing potential may be enrolled in the study if the participant (for the Shingrix® sub-study only):
  • Has practiced adequate contraception for 30 days prior to vaccination; and
  • Has a negative urine pregnancy test on the day of the first vaccination; and
  • Has agreed to continue adequate contraception during the primary treatment period and for 2 months after completion of the vaccination series (Week 16)
  • Patients must have a history of prior chicken pox (for the Zostavax® sub-study only; for patients who do not recall prior chicken pox, a positive varicella IgG serology can be used to document prior exposure)

Exclusion criteria include:

  • prior Zostavax® receipt (for the Zostavax® sub-study only; the Shingrix® sub-study will allow prior Zostavax® receipt if 6 months or greater prior to enrollment)
  • 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) [NOTE: this exclusion applies only for the Zostavax® portion of the study]
  • methotrexate use > 25 mg/week
  • 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 (within the last 30 days) of anti-viral medications against the herpesvirus family
  • Received any live virus vaccine within 28 days prior to study entry (Zostavax® sub-study only)
  • Administration or planned administration of any live vaccine <28 days before the first study vaccination or through 28 days after the second study vaccination (Shingrix ® sub-study only)
  • received any inactivated vaccine within 7 days prior to study entry (Zostavax® sub-study only)
  • Received any inactivated vaccine +/- 14 days of each study injection (Shingrix ® sub-study only)
  • known household contacts who may be susceptible to a live virus vaccine (e.g. pregnant women) [NOTE: this exclusion for the Zostavax® sub-study only]

Sites / Locations

  • St. Luke's Health SystemRecruiting
  • St. Paul RheumatologyRecruiting
  • Jayashree Sinha, MDRecruiting
  • Oregon Health & Science UniversityRecruiting
  • Arthritis AssociatesRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Arm Label

Varicella Zoster Vaccine (Zostavax)

Placebo Injection (Zostavax Comparator)

Varicella Zoster Vaccine (Shingrix)

Placebo Injection (Shingrix Comparator)

Arm Description

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

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

Non-live zoster vaccine injection will be administered twice, 8 weeks apart, as a single 0.65-mL dose subcutaneously in the deltoid region of the upper arm at the baseline visit

Saline injection will be administered twice, 8 weeks apart, as a single 0.65-mL dose subcutaneously in the deltoid region of the upper arm at the baseline visit

Outcomes

Primary Outcome Measures

Change in ELISPOT response from baseline to week 6, and one 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.
Change in IgG titer from baseline to week 6, and one 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

Development of Varicella Zoster Virus
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.

Full Information

First Posted
July 5, 2018
Last Updated
March 16, 2023
Sponsor
Kevin Winthrop
Collaborators
University of Alabama at Birmingham, Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT03604406
Brief Title
The Immunogenicity and Safety of Zostavax® and Shingrix® in Rheumatoid Arthritis Patients Using Abatacept
Acronym
BMS-188667
Official Title
The Immunogenicity and Safety of Zostavax® and Shingrix® in Rheumatoid Arthritis Patients Using Abatacept
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 8, 2014 (Actual)
Primary Completion Date
July 2023 (Anticipated)
Study Completion Date
June 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Kevin Winthrop
Collaborators
University of Alabama at Birmingham, Bristol-Myers Squibb

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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 or Shingrix are 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.
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 these vaccines. 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. An additional non-live vaccine, the adjuvanted recombinant glycoprotein E (gE) herpes zoster (HZ) vaccine (recombinant zoster vaccine; RZV; Shingrix®), has recently been approved for healthy immunocompetent adults >50 years old by the Advisory Committee on Immunization Practices (ACIP). In pivotal trials among healthy individuals, the vaccine was more than 90% effective in all age groups studied (>50 years) with a low incidence of serious adverse events. However, the vaccine displayed a high degree of reactogenicity with 15.6% of individuals suffering grade 3 or higher systemic reactions. While these reactions were self-limited and typically resolved within several days, patients with active immune-mediated inflammatory diseases (e.g. RA) were not included in these trials. There is concern that given the potency of the AS01B adjuvant in RZV and its subsequent reactogenicity, that vaccination with RZV could result in flares of underlying inflammatory diseases. Further, it is unclear how biologic therapy affects the immunogenicity or reactogenicity of this vaccine, and it is possible the efficacy of this vaccine will not be as high in immunosuppressed populations. Given RZV is a non-live vaccine, it theoretically has advantage over the currently used live shingles vaccine in which it is contraindicated to give to patients using biologic therapy. However, before such use is recommended, the vaccine should be evaluated in such populations.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Herpes Zoster, Inflammatory Disease, Rheumatoid Arthritis
Keywords
Shingles, abatacept, Varicella Zoster Vaccine

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
130 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Varicella Zoster Vaccine (Zostavax)
Arm Type
Experimental
Arm Description
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
Arm Title
Placebo Injection (Zostavax Comparator)
Arm Type
Placebo Comparator
Arm Description
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
Arm Title
Varicella Zoster Vaccine (Shingrix)
Arm Type
Experimental
Arm Description
Non-live zoster vaccine injection will be administered twice, 8 weeks apart, as a single 0.65-mL dose subcutaneously in the deltoid region of the upper arm at the baseline visit
Arm Title
Placebo Injection (Shingrix Comparator)
Arm Type
Placebo Comparator
Arm Description
Saline injection will be administered twice, 8 weeks apart, as a single 0.65-mL dose subcutaneously in the deltoid region of the upper arm at the baseline visit
Intervention Type
Biological
Intervention Name(s)
Varicella Zoster Vaccine
Other Intervention Name(s)
Zostavax
Intervention Description
live-attenuated vaccine to prevent herpes zoster
Intervention Type
Other
Intervention Name(s)
Placebo Injection
Intervention Description
Saline solution injection
Intervention Type
Biological
Intervention Name(s)
Varicella Zoster Vaccine
Other Intervention Name(s)
Shingrix
Intervention Description
non-live vaccine to prevent herpes zoster
Primary Outcome Measure Information:
Title
Change in ELISPOT response from baseline to week 6, and one year post vaccination
Description
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.
Time Frame
1) Baseline visit prior to vaccination; 2) 6 weeks post-vaccination; 3) 1 year post-vaccination
Title
Change in IgG titer from baseline to week 6, and one year post vaccination
Description
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.
Time Frame
1) Baseline visit prior to vaccination; 2) 6 weeks post-vaccination; 3) 1 year post-vaccination
Secondary Outcome Measure Information:
Title
Development of Varicella Zoster Virus
Description
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.
Time Frame
Within 42 days of vaccination

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria include: be >= 50 years of age or older (for the Zostavax® sub-study only) be >= 18 years of age or older (for the Shingrix® sub-study only) be 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 (for the Zostavax® sub-study only). Female participants of childbearing potential may be enrolled in the study if the participant (for the Shingrix® sub-study only): Has practiced adequate contraception for 30 days prior to vaccination; and Has a negative urine pregnancy test on the day of the first vaccination; and Has agreed to continue adequate contraception during the primary treatment period and for 2 months after completion of the vaccination series (Week 16) Patients must have a history of prior chicken pox (for the Zostavax® sub-study only; for patients who do not recall prior chicken pox, a positive varicella IgG serology can be used to document prior exposure) Exclusion criteria include: prior Zostavax® receipt (for the Zostavax® sub-study only; the Shingrix® sub-study will allow prior Zostavax® receipt if 6 months or greater prior to enrollment) 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) [NOTE: this exclusion applies only for the Zostavax® portion of the study] methotrexate use > 25 mg/week 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 (within the last 30 days) of anti-viral medications against the herpesvirus family Received any live virus vaccine within 28 days prior to study entry (Zostavax® sub-study only) Administration or planned administration of any live vaccine <28 days before the first study vaccination or through 28 days after the second study vaccination (Shingrix ® sub-study only) received any inactivated vaccine within 7 days prior to study entry (Zostavax® sub-study only) Received any inactivated vaccine +/- 14 days of each study injection (Shingrix ® sub-study only) known household contacts who may be susceptible to a live virus vaccine (e.g. pregnant women) [NOTE: this exclusion for the Zostavax® sub-study only]
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ryan Stadnik, MPH
Phone
503-494-3560
Email
stadnikr@ohsu.edu
Facility Information:
Facility Name
St. Luke's Health System
City
Boise
State/Province
Idaho
ZIP/Postal Code
83702
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Cari Cardoni, RN, BSN
Phone
208-706-9086
Email
cardonic@slhs.org
Facility Name
St. Paul Rheumatology
City
Eagan
State/Province
Minnesota
ZIP/Postal Code
55121
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yolanda Fabelo
Phone
651-361-8659
Email
margarita@sprderm.com
Facility Name
Jayashree Sinha, MD
City
Clovis
State/Province
New Mexico
ZIP/Postal Code
88101
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Iantha Hicks
Email
l.hicks@aara.care
Facility Name
Oregon Health & Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ryan Stadnik, MPH
Phone
503-494-3560
Email
stadnikr@ohsu.edu
First Name & Middle Initial & Last Name & Degree
Kevin L Winthrop, MD, MPH
Facility Name
Arthritis Associates
City
Hixson
State/Province
Tennessee
ZIP/Postal Code
37343
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joseph Huffstutter, MD
Phone
423-886-9641
Email
jhuff@arthchatt.com

12. IPD Sharing Statement

Learn more about this trial

The Immunogenicity and Safety of Zostavax® and Shingrix® in Rheumatoid Arthritis Patients Using Abatacept

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