<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03016884</url>
  </required_header>
  <id_info>
    <org_study_id>142-016-EMC</org_study_id>
    <nct_id>NCT03016884</nct_id>
  </id_info>
  <brief_title>Safety and Tolerability of Herpes Zoster Vaccine Rheumatologic Patients</brief_title>
  <official_title>Safety and Tolerability of Herpes Zoster Vaccine in Patients With Rheumatoid Arthritis Immunized Prior to Biologics and Tofacitinib Therapy Initiation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>HaEmek Medical Center, Israel</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>HaEmek Medical Center, Israel</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The reactivation of varicella zoster virus (VZV) (herpes zoster (HZ)) is of substantial&#xD;
      public health concern. Updated ACR recommendations for RA treatment suggest that RA patients&#xD;
      aged ≥ 50 years should be vaccinated before receiving biologic or tofacitinib therapy. The&#xD;
      Investigators therefore propose a prospective study to evaluate the safety, tolerability, and&#xD;
      immunogenicity of a zoster vaccine (Zostavax) in patients with RA, administered at least 2&#xD;
      weeks prior to initiation of anti-TNF biologic and tofacitinib therapy for RA.&#xD;
&#xD;
      This is a 6-week open-label prospective multi-center study evaluating the safety,&#xD;
      tolerability, and immunogenicity of Zostavax vaccine in the RA population prior to initiation&#xD;
      of biologic/tofacitinib therapy for RA. VZV-specific immune response to vaccine in RA&#xD;
      patients will be compared to healthy control subjects ≥ 50 years immunized with Zostavax.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Safety and Tolerability of Herpes Zoster Vaccine in Patients with Rheumatoid Arthritis&#xD;
      Immunized prior to biologics and tofacitinib therapy initiation Background The reactivation&#xD;
      of varicella zoster virus (VZV) (herpes zoster (HZ)) is of substantial public health concern.&#xD;
      Its predilection for the elderly and immunosuppressed make it an important cause of&#xD;
      morbidity, causing pain, depression, and long-term disability in the form of post-herpetic&#xD;
      neuralgia. The risk of HZ is increased by 1.5 to 2 times in patients with rheumatoid&#xD;
      arthritis (RA) compared with the general population.This increase has been attributed to both&#xD;
      the underlying disease process and treatments for RA, in particular, corticosteroids, TNFα&#xD;
      blocking agents, rituximab, and tofacitinib.&#xD;
&#xD;
      A live attenuated zoster vaccine, administered as a single subcutaneous injection, reduces HZ&#xD;
      risk by 70% and 51% among immunocompetent individuals 50 to 59 years and 60 years and older&#xD;
      in 2 randomized blinded trials, respectively.&#xD;
&#xD;
      Updated ACR recommendations for RA treatment suggest that RA patients aged ≥ 50 years should&#xD;
      be vaccinated before receiving biologic or tofacitinib therapy. Yet, the real world data&#xD;
      proves that only minority of RA patients initiating biologic therapy are vaccinated for&#xD;
      herpes zoster.&#xD;
&#xD;
      The safety concern is that these individuals may develop varicella infection from the vaccine&#xD;
      virus strain. Recently, zoster vaccine safety, tolerability, and immunogenicity were&#xD;
      prospectively tested in patients on chronic low-medium dose of corticosteroid therapy. Zoster&#xD;
      vaccine was generally well tolerated and immunogenic in this patient population.&#xD;
&#xD;
      Based on the VZV incubation period, the first 42 days following vaccination was chosen as the&#xD;
      primary safety risk window in the Shingles Prevention Study, a randomized blinded trial that&#xD;
      preceded the FDA approval of the vaccine.&#xD;
&#xD;
      The investigators therefore propose a prospective study to evaluate the safety, tolerability,&#xD;
      and immunogenicity of a zoster vaccine (Zostavax) in patients with RA, administered at least&#xD;
      2 weeks prior to initiation of anti-TNF biologic and tofacitinib therapy for RA. The study&#xD;
      will specifically focus on the zoster vaccine related adverse events, including injection&#xD;
      site reactions, the development of zoster-like lesions, and the rates of clinical herpes&#xD;
      zoster.&#xD;
&#xD;
      Study Objective:&#xD;
&#xD;
        1. To evaluate the rate of adverse reactions, injection site reactions, and development of&#xD;
           zoster-like lesions following Zostavax administration.&#xD;
&#xD;
        2. To evaluate the rate of clinical herpes zoster events after initiation of biologic and&#xD;
           small molecule therapies for RA following Zostavax administration.&#xD;
&#xD;
        3. To evaluate the immunogenicity of Zostavax in RA patients immunized 2 weeks prior to&#xD;
           biologic or tofacitinib therapy.&#xD;
&#xD;
      Study Design:&#xD;
&#xD;
      This is a 6-week open-label prospective multi-center study evaluating the safety,&#xD;
      tolerability, and immunogenicity of Zostavax vaccine in the RA population prior to initiation&#xD;
      of biologic/tofacitinib therapy for RA. VZV-specific immune response to vaccine in RA&#xD;
      patients will be compared to healthy control subjects ≥ 50 years immunized with Zostavax.&#xD;
&#xD;
      Healthy volunteers will be recruited from hospital staff and from relatives of patients who&#xD;
      agreed to participate in this studyNine Rheumatology Departments across Israel only will&#xD;
      participate in the study. These centers are Tel Aviv Medical Center, Sheba Medical Center,&#xD;
      Assaf Harofe Medical Center, Shaare Zedek Medical Center, Rabin Medical Center, Bnei Tsion&#xD;
      Medical Center, Rambam MedicaL Center, Hahemek Medical center, Carmel Medical Center.&#xD;
&#xD;
      Vaccine Information:&#xD;
&#xD;
      ZOSTAVAX is a lyophilized preparation of live, attenuated varicella-zoster virus (Oka/Merck&#xD;
      strain) to be reconstituted with sterile diluent to give a single dose suspension with a&#xD;
      minimum of 19,400 PFU (plaque forming units) when stored at room temperature for up to 30&#xD;
      minutes. It is administered as a single subcutaneous injection into the deltoid region of the&#xD;
      upper arm.&#xD;
&#xD;
      Study Visits:&#xD;
&#xD;
      Screening Visit/Vaccination The study Investigator will discuss, with each subject, the&#xD;
      nature of the study, its requirements, and its restrictions. Written informed consent must be&#xD;
      obtained prior performance of any protocol specific procedures. Upon recruitment, patients&#xD;
      will be examined by a treating rheumatologist, in order to verify the diagnosis of RA and&#xD;
      review the pertinent to vaccination medical history. Patients will be subsequently assessed&#xD;
      for RA disease activity.&#xD;
&#xD;
      Procedures to be performed during the screening period include:&#xD;
&#xD;
      Informed Consent Confirmation of RA diagnosis and Classification of RA: subject must have a&#xD;
      score of 6 or greater on the 2010 American College of Rheumatology/European League Against&#xD;
      Rheumatism classification criteria for rheumatoid arthritis Medical History as pertinent to&#xD;
      HZ vaccination including history of prior and concomitant medications, history of any prior&#xD;
      episodes of herpes zoster, and zoster vaccine history.&#xD;
&#xD;
      Assessment of RA activity:&#xD;
&#xD;
      Blood test (ESR, CRP), varicella-zoster virus (VZV) antibody titers by glycoprotein&#xD;
      enzyme-linked immunosorbent assay (gpELISA), (will be carried out centrally at tel Aviv&#xD;
      Sourasky medical center Immunology laboratory) and future analysis (excluding any genetic&#xD;
      tests).&#xD;
&#xD;
      After the screening, the eligible patients who provided the informed consent, will be&#xD;
      administered the zoster vaccine.&#xD;
&#xD;
      2- week phone interview based follow up/ Biologic or tofacitinib treatment initiation&#xD;
      (etanercept and tofacitinib will comprise 80% of total therapies) At the 2-week visit,&#xD;
      vaccine safety will be assessed. Following a two-week interval from the zoster vaccine&#xD;
      administration, biologic or tofacitinib treatment will be initiated as scheduled by a&#xD;
      treating rheumatologist.&#xD;
&#xD;
      Importantly, no biologic treatment of any kind would be provided by the study project.&#xD;
&#xD;
      4- week phone interview follow up Vaccine safety and adverse effects assessment. 6- week&#xD;
      visit Vaccine safety and adverse effects assessment. Assessment of RA activity. Subject&#xD;
      Withdrawal Subjects may withdraw from the study at any time at their own request.&#xD;
&#xD;
      Assessments:&#xD;
&#xD;
      Assessment of RA Disease Activity At each study visit, patients will be subsequently assessed&#xD;
      for RA disease activity Patient Assessment of Arthritis Pain Patient Global Assessment of&#xD;
      Arthritis. Physician Global Assessment of Arthritis Health Assessment Questionnaire -&#xD;
      Disability Index (HAQ-DI) Safety Assessment Any adverse reactions/events following zoster&#xD;
      vaccine administration will be registered and assessed.&#xD;
&#xD;
      Injection site adverse reactions:&#xD;
&#xD;
      Local pain/erythema/swelling/pruritus/warmth/hematoma/induration Hypersensitivity Post&#xD;
      vaccination non-injection-site zoster-like and varicella-like rashes Post vaccination herpes&#xD;
      zoster occurrence Systemic adverse reactions Progression/worsening of underlying disease&#xD;
&#xD;
      Adverse effects will be defined according to the following definitions:&#xD;
&#xD;
      MILD Does not interfere with subject's usual function. MODERATE Interferes to some extent&#xD;
      with subject's usual function. SEVERE Interferes significantly with subject's usual function.&#xD;
&#xD;
      Blood tests Samples of 15 cc blood only will be taken at two visits: pre-vaccination and&#xD;
      post-vaccination (6 weeks). VZV antibody titers will be measured by commercially available&#xD;
      ELISA kits.&#xD;
&#xD;
      All data will be deidentified. Only the principal investigator will have access to the table&#xD;
      key linking the data sets with personally identifiable information. The study documents will&#xD;
      be kept locked at department of rheumatology. The study will be financed by the research&#xD;
      funds of the principal investigator.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">January 2017</start_date>
  <completion_date type="Anticipated">July 2020</completion_date>
  <primary_completion_date type="Actual">September 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of patients with Injection site adverse reactions</measure>
    <time_frame>6 weeks</time_frame>
    <description>collecting number of patients with injection site adverse reactions defined as: Local pain/erythema/swelling/pruritus/warmth/hematoma/induration will be assessed by the investigators at follow up visit, and will be asked by phone call.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of patients with Hypersensitivity</measure>
    <time_frame>6 weeks</time_frame>
    <description>collecting number of patients with hypersensitivity adverse reactions defined as: Any immediate systemic reactions such as anaphylactic reaction, fever, low blood pressure, drug induced rash or urticaria, nausea and vomiting, diarrhea data will be collected at the visit of injection administration, and by phone call 2 weeks past the vaccination</description>
  </primary_outcome>
  <primary_outcome>
    <measure>number of patients with Post vaccination non-injection-site zoster-like and varicella-like rashes</measure>
    <time_frame>6 weeks</time_frame>
    <description>collecting number of patients with non-injection-site zoster-like and varicella-like rash will be defined as adverse reaction. will be assessed by investigator by phone follow up and at 6 weeks follow up meeting.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of patients with Post vaccination herpes zoster occurrence</measure>
    <time_frame>6 weeks</time_frame>
    <description>collecting number of patients with Post vaccination herpes zoster occurrence will be defined as adverse reaction. will be assessed by investigator by phone follow up and at 6 weeks follow up meeting.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Immunogenicity measured by varicella-zoster virus (VZV) antibody titers by glycoprotein enzyme-linked immunosorbent assay (gpELISA)</measure>
    <time_frame>6 weeks</time_frame>
    <description>of 15 cc blood only will be taken at two visits: pre-vaccination and post-vaccination (6 weeks). Serum will be separated, aliquoted and stored frozen at -20°C until analysis. The serum samples will be stored and tested in the TASMC Laboratory for Arthritis Research. VZV antibody titers will be measured by commercially available ELISA kits. Any other analyses of the serum samples in the future will only be performed after obtaining permission from the institutional ethics committee, as required by law. No genetic test will be performed. The serum samples will not be taken outside of the Tel Aviv Medical Center, unless specific permission is obtained from the institutional ethics committee in the future. Samples of 15 cc blood only will be taken at two visits: pre-vaccination and post-vaccination (6 weeks). Serum will be separated, aliquoted and stored frozen at -20°C until analysis. The serum samples will be stored and tested in the TASMC Laboratory for Arthritis Research. VZV antibody</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tender and Swollen Joint Count (28 joint count)</measure>
    <time_frame>6 weeks</time_frame>
    <description>Twenty-eight (28) joints will be assessed by a physician to determine the number of joints that are considered tender/painful. The response to pressure/motion on each joint will be assessed using the following scale: Present/Absent/Not Done/Not Applicable (to be used for artificial joints). These joints will be further assessed for swelling using the same scale.&#xD;
The 28 joints to be assessed are the shoulders, elbows, wrists, metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, and knees. Artificial joints will not be assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient Assessment of Arthritis Pain</measure>
    <time_frame>6 weeks</time_frame>
    <description>Participants will assess the severity of their arthritis pain using a 100 mm visual analog scale (VAS) placing a mark on the scale between 0 (no pain) and 100 (most severe pain), which corresponds to the magnitude of their pain.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient Global Assessment of Arthritis</measure>
    <time_frame>6 weeks</time_frame>
    <description>Participants will answer the following question, &quot;Considering all the ways your arthritis affects you, how are you feeling today?&quot; The subject's response will be recorded using a 100 mm VAS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physician Global Assessment of Arthritis</measure>
    <time_frame>6 weeks</time_frame>
    <description>The physician will assess how the subject's overall arthritis appears at the time of the visit. This is an evaluation based on the subject's disease signs, functional capacity and physical examination, and should be independent of the Patient's Global Assessment of Arthritis. The Investigator's response will be recorded using a 100 mm VAS.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health Assessment Questionnaire - Disability Index (HAQ-DI)</measure>
    <time_frame>6 weeks</time_frame>
    <description>The HAQ-DI assesses the degree of difficulty a subject has experienced during the past week in 8 domains of daily living activities: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other activities.13 Each activity category consists of 2-3 items. For each question in the questionnaire, the level of difficulty is scored from 0 to 3 with 0 representing &quot;no difficulty,&quot; 1 as &quot;some difficulty,&quot; 2 as &quot;much difficulty,&quot; and 3 as &quot;unable to do&quot;. Any activity that requires assistance from another individual or requires the use of an assistive device adjusts to a minimum score of 2 to represent a more limited functional status. The form should then be checked by the site staff for completeness.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">87</enrollment>
  <condition>Herpes Zoster</condition>
  <arm_group>
    <arm_group_label>RA patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>RA patients will be administered Zostavax vaccine once 2 weeks before initiation of bDMARD, and be monitored accordingly</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy Controls</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>healthy control patients will be administered Zostavax vaccine and be monitored accordingly</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Zostavax vaccine</intervention_name>
    <description>After the screening, the eligible patients who provided the informed consent, will be administered the zoster vaccine.</description>
    <arm_group_label>Healthy Controls</arm_group_label>
    <arm_group_label>RA patients</arm_group_label>
    <other_name>ZOSTAVAX® (Zoster Vaccine Live)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        For RA arm:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          1. Evidence of a personally signed and dated informed consent document indicating that&#xD;
             the subject (or a legally acceptable representative) has been informed of all&#xD;
             pertinent aspects of the study.&#xD;
&#xD;
          2. Patients fulfilling the 2010 American College of Rheumatology/European League Against&#xD;
             Rheumatism Classification Criteria for RA scheduled for a biologic or small molecule&#xD;
             therapy (80% candidates for etanercept or tofacitinib therapies.)&#xD;
&#xD;
          3. Only subjects who are ≥ 50 years old will be administered the zoster vaccine.&#xD;
&#xD;
          4. Subjects who are willing and able to comply with scheduled visits and other study&#xD;
             procedures&#xD;
&#xD;
          5. Patients on biologics may participate after a washout period as indicated below :&#xD;
&#xD;
               1. Etanercept : 2 weeks&#xD;
&#xD;
               2. Infliximab, Golimumab, Adalimumab : 35 days&#xD;
&#xD;
               3. Tocilizumab and Abatacept SC : 2 weeks&#xD;
&#xD;
               4. Tocilizumab and Abatacept IV : 35 days&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. History of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other&#xD;
             component of the vaccine.&#xD;
&#xD;
          2. Previous vaccination with any VZV-containing vaccine.&#xD;
&#xD;
          3. Any type of malignancy, ongoing chemotherapy or radiation therapy.&#xD;
&#xD;
          4. Patients who underwent solid organ transplantation.&#xD;
&#xD;
          5. Patients with AIDS or clinical manifestations of HIV&#xD;
&#xD;
          6. Patients treated with a TNFa inhibitor at the time of recruitment or patients within a&#xD;
             year of rituximab administration.&#xD;
&#xD;
          7. Patients receiving daily corticosteroid therapy with a dose ≥10 mg/day of prednisone&#xD;
             (or equivalent) for ≥ 14 days and/or methotrexate at the dose above 0.4 mg per kg per&#xD;
             week.&#xD;
&#xD;
          8. Patients with an active herpes zoster infection or previous herpes zoster less than 6&#xD;
             months before recruitment.&#xD;
&#xD;
          9. Vaccination with any live vaccine within 4 weeks prevaccination, any inactivated&#xD;
             vaccine within 7 days prevaccination, or either during the study period.&#xD;
&#xD;
         10. Blood products transfusion within 5 months prior to vaccination through the study&#xD;
             period.&#xD;
&#xD;
         11. Patients with active tuberculosis.&#xD;
&#xD;
         12. History of Guillain-Barre Syndrome&#xD;
&#xD;
        for healthy arm: Inclusion subjects who are ≥ 50 years old will be administered the zoster&#xD;
        vaccine.&#xD;
&#xD;
        Exclusion&#xD;
&#xD;
          1. History of past or present autoimmune diseases&#xD;
&#xD;
          2. History or current use of immunosuppressive drugs&#xD;
&#xD;
          3. History of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other&#xD;
             component of the vaccine.&#xD;
&#xD;
          4. .Previous vaccination with any VZV-containing vaccine.&#xD;
&#xD;
          5. Any type of malignancy, ongoing chemotherapy or radiation therapy.&#xD;
&#xD;
          6. History of underwent solid organ transplantation.&#xD;
&#xD;
          7. Active herpes zoster infection or previous herpes zoster less than 6 months before&#xD;
             recruitment.&#xD;
&#xD;
          8. Vaccination with any live vaccine within 4 weeks prevaccination, any inactivated&#xD;
             vaccine within 7 days prevaccination, or either during the study period.&#xD;
&#xD;
          9. Blood products transfusion within 5 months prior to vaccination through the study&#xD;
             period.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Ha'Emek Medical center, Unit of Rheumatology</name>
      <address>
        <city>Afula</city>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Carmel Medical Center</name>
      <address>
        <city>Haifa</city>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tel Aviv Medical Center, Unit pf Rheumatology</name>
      <address>
        <city>Tel Aviv</city>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <reference>
    <citation>Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA, Chan KA. The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom. Arthritis Rheum. 2007 Dec 15;57(8):1431-8. doi: 10.1002/art.23112.</citation>
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  <reference>
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  </reference>
  <reference>
    <citation>Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, Moreland LW, O'Dell J, Winthrop KL, Beukelman T, Bridges SL Jr, Chatham WW, Paulus HE, Suarez-Almazor M, Bombardier C, Dougados M, Khanna D, King CM, Leong AL, Matteson EL, Schousboe JT, Moynihan E, Kolba KS, Jain A, Volkmann ER, Agrawal H, Bae S, Mudano AS, Patkar NM, Saag KG. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012 May;64(5):625-39. doi: 10.1002/acr.21641. No abstract available.</citation>
    <PMID>22473917</PMID>
  </reference>
  <reference>
    <citation>Russell AF, Parrino J, Fisher CL Jr, Spieler W, Stek JE, Coll KE, Su SC, Xu J, Li X, Schlienger K, Silber JL. Safety, tolerability, and immunogenicity of zoster vaccine in subjects on chronic/maintenance corticosteroids. Vaccine. 2015 Jun 17;33(27):3129-34. doi: 10.1016/j.vaccine.2015.04.090. Epub 2015 May 8.</citation>
    <PMID>25964168</PMID>
  </reference>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>January 1, 2017</study_first_submitted>
  <study_first_submitted_qc>January 8, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 11, 2017</study_first_posted>
  <last_update_submitted>February 18, 2020</last_update_submitted>
  <last_update_submitted_qc>February 18, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 19, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Herpes Zoster</keyword>
  <keyword>anti TNF alpha</keyword>
  <keyword>tofacitinib</keyword>
  <keyword>Rheumatoid Arthritis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Herpes Simplex</mesh_term>
    <mesh_term>Herpes Zoster</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vaccines</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03016884
org study id: 142-016-EMC
nct id: NCT03016884
lead sponsor: 
has dmc: No
The reactivation of varicella zoster virus (VZV) (herpes zoster (HZ)) is of substantial
      public health concern. Updated ACR recommendations for RA treatment suggest that RA patients
      aged ≥ 50 years should be vaccinated before receiving biologic or tofacitinib therapy. The
      Investigators therefore propose a prospective study to evaluate the safety, tolerability, and
      immunogenicity of a zoster vaccine (Zostavax) in patients with RA, administered at least 2
      weeks prior to initiation of anti-TNF biologic and tofacitinib therapy for RA.

      This is a 6-week open-label prospective multi-center study evaluating the safety,
      tolerability, and immunogenicity of Zostavax vaccine in the RA population prior to initiation
      of biologic/tofacitinib therapy for RA. VZV-specific immune response to vaccine in RA
      patients will be compared to healthy control subjects ≥ 50 years immunized with Zostavax.
Safety and Tolerability of Herpes Zoster Vaccine in Patients with Rheumatoid Arthritis
      Immunized prior to biologics and tofacitinib therapy initiation Background The reactivation
      of varicella zoster virus (VZV) (herpes zoster (HZ)) is of substantial public health concern.
      Its predilection for the elderly and immunosuppressed make it an important cause of
      morbidity, causing pain, depression, and long-term disability in the form of post-herpetic
      neuralgia. The risk of HZ is increased by 1.5 to 2 times in patients with rheumatoid
      arthritis (RA) compared with the general population.This increase has been attributed to both
      the underlying disease process and treatments for RA, in particular, corticosteroids, TNFα
      blocking agents, rituximab, and tofacitinib.

      A live attenuated zoster vaccine, administered as a single subcutaneous injection, reduces HZ
      risk by 70% and 51% among immunocompetent individuals 50 to 59 years and 60 years and older
      in 2 randomized blinded trials, respectively.

      Updated ACR recommendations for RA treatment suggest that RA patients aged ≥ 50 years should
      be vaccinated before receiving biologic or tofacitinib therapy. Yet, the real world data
      proves that only minority of RA patients initiating biologic therapy are vaccinated for
      herpes zoster.

      The safety concern is that these individuals may develop varicella infection from the vaccine
      virus strain. Recently, zoster vaccine safety, tolerability, and immunogenicity were
      prospectively tested in patients on chronic low-medium dose of corticosteroid therapy. Zoster
      vaccine was generally well tolerated and immunogenic in this patient population.

      Based on the VZV incubation period, the first 42 days following vaccination was chosen as the
      primary safety risk window in the Shingles Prevention Study, a randomized blinded trial that
      preceded the FDA approval of the vaccine.

      The investigators therefore propose a prospective study to evaluate the safety, tolerability,
      and immunogenicity of a zoster vaccine (Zostavax) in patients with RA, administered at least
      2 weeks prior to initiation of anti-TNF biologic and tofacitinib therapy for RA. The study
      will specifically focus on the zoster vaccine related adverse events, including injection
      site reactions, the development of zoster-like lesions, and the rates of clinical herpes
      zoster.

      Study Objective:

        1. To evaluate the rate of adverse reactions, injection site reactions, and development of
           zoster-like lesions following Zostavax administration.

        2. To evaluate the rate of clinical herpes zoster events after initiation of biologic and
           small molecule therapies for RA following Zostavax administration.

        3. To evaluate the immunogenicity of Zostavax in RA patients immunized 2 weeks prior to
           biologic or tofacitinib therapy.

      Study Design:

      This is a 6-week open-label prospective multi-center study evaluating the safety,
      tolerability, and immunogenicity of Zostavax vaccine in the RA population prior to initiation
      of biologic/tofacitinib therapy for RA. VZV-specific immune response to vaccine in RA
      patients will be compared to healthy control subjects ≥ 50 years immunized with Zostavax.

      Healthy volunteers will be recruited from hospital staff and from relatives of patients who
      agreed to participate in this studyNine Rheumatology Departments across Israel only will
      participate in the study. These centers are Tel Aviv Medical Center, Sheba Medical Center,
      Assaf Harofe Medical Center, Shaare Zedek Medical Center, Rabin Medical Center, Bnei Tsion
      Medical Center, Rambam MedicaL Center, Hahemek Medical center, Carmel Medical Center.

      Vaccine Information:

      ZOSTAVAX is a lyophilized preparation of live, attenuated varicella-zoster virus (Oka/Merck
      strain) to be reconstituted with sterile diluent to give a single dose suspension with a
      minimum of 19,400 PFU (plaque forming units) when stored at room temperature for up to 30
      minutes. It is administered as a single subcutaneous injection into the deltoid region of the
      upper arm.

      Study Visits:

      Screening Visit/Vaccination The study Investigator will discuss, with each subject, the
      nature of the study, its requirements, and its restrictions. Written informed consent must be
      obtained prior performance of any protocol specific procedures. Upon recruitment, patients
      will be examined by a treating rheumatologist, in order to verify the diagnosis of RA and
      review the pertinent to vaccination medical history. Patients will be subsequently assessed
      for RA disease activity.

      Procedures to be performed during the screening period include:

      Informed Consent Confirmation of RA diagnosis and Classification of RA: subject must have a
      score of 6 or greater on the 2010 American College of Rheumatology/European League Against
      Rheumatism classification criteria for rheumatoid arthritis Medical History as pertinent to
      HZ vaccination including history of prior and concomitant medications, history of any prior
      episodes of herpes zoster, and zoster vaccine history.

      Assessment of RA activity:

      Blood test (ESR, CRP), varicella-zoster virus (VZV) antibody titers by glycoprotein
      enzyme-linked immunosorbent assay (gpELISA), (will be carried out centrally at tel Aviv
      Sourasky medical center Immunology laboratory) and future analysis (excluding any genetic
      tests).

      After the screening, the eligible patients who provided the informed consent, will be
      administered the zoster vaccine.

      2- week phone interview based follow up/ Biologic or tofacitinib treatment initiation
      (etanercept and tofacitinib will comprise 80% of total therapies) At the 2-week visit,
      vaccine safety will be assessed. Following a two-week interval from the zoster vaccine
      administration, biologic or tofacitinib treatment will be initiated as scheduled by a
      treating rheumatologist.

      Importantly, no biologic treatment of any kind would be provided by the study project.

      4- week phone interview follow up Vaccine safety and adverse effects assessment. 6- week
      visit Vaccine safety and adverse effects assessment. Assessment of RA activity. Subject
      Withdrawal Subjects may withdraw from the study at any time at their own request.

      Assessments:

      Assessment of RA Disease Activity At each study visit, patients will be subsequently assessed
      for RA disease activity Patient Assessment of Arthritis Pain Patient Global Assessment of
      Arthritis. Physician Global Assessment of Arthritis Health Assessment Questionnaire -
      Disability Index (HAQ-DI) Safety Assessment Any adverse reactions/events following zoster
      vaccine administration will be registered and assessed.

      Injection site adverse reactions:

      Local pain/erythema/swelling/pruritus/warmth/hematoma/induration Hypersensitivity Post
      vaccination non-injection-site zoster-like and varicella-like rashes Post vaccination herpes
      zoster occurrence Systemic adverse reactions Progression/worsening of underlying disease

      Adverse effects will be defined according to the following definitions:

      MILD Does not interfere with subject's usual function. MODERATE Interferes to some extent
      with subject's usual function. SEVERE Interferes significantly with subject's usual function.

      Blood tests Samples of 15 cc blood only will be taken at two visits: pre-vaccination and
      post-vaccination (6 weeks). VZV antibody titers will be measured by commercially available
      ELISA kits.

      All data will be deidentified. Only the principal investigator will have access to the table
      key linking the data sets with personally identifiable information. The study documents will
      be kept locked at department of rheumatology. The study will be financed by the research
      funds of the principal investigator.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Number of patients with Injection site adverse reactions
time frame: 6 weeks
description: collecting number of patients with injection site adverse reactions defined as: Local pain/erythema/swelling/pruritus/warmth/hematoma/induration will be assessed by the investigators at follow up visit, and will be asked by phone call.
measure: Number of patients with Hypersensitivity
time frame: 6 weeks
description: collecting number of patients with hypersensitivity adverse reactions defined as: Any immediate systemic reactions such as anaphylactic reaction, fever, low blood pressure, drug induced rash or urticaria, nausea and vomiting, diarrhea data will be collected at the visit of injection administration, and by phone call 2 weeks past the vaccination
measure: number of patients with Post vaccination non-injection-site zoster-like and varicella-like rashes
time frame: 6 weeks
description: collecting number of patients with non-injection-site zoster-like and varicella-like rash will be defined as adverse reaction. will be assessed by investigator by phone follow up and at 6 weeks follow up meeting.
measure: Number of patients with Post vaccination herpes zoster occurrence
time frame: 6 weeks
description: collecting number of patients with Post vaccination herpes zoster occurrence will be defined as adverse reaction. will be assessed by investigator by phone follow up and at 6 weeks follow up meeting.
measure: Immunogenicity measured by varicella-zoster virus (VZV) antibody titers by glycoprotein enzyme-linked immunosorbent assay (gpELISA)
time frame: 6 weeks
description: of 15 cc blood only will be taken at two visits: pre-vaccination and post-vaccination (6 weeks). Serum will be separated, aliquoted and stored frozen at -20°C until analysis. The serum samples will be stored and tested in the TASMC Laboratory for Arthritis Research. VZV antibody titers will be measured by commercially available ELISA kits. Any other analyses of the serum samples in the future will only be performed after obtaining permission from the institutional ethics committee, as required by law. No genetic test will be performed. The serum samples will not be taken outside of the Tel Aviv Medical Center, unless specific permission is obtained from the institutional ethics committee in the future. Samples of 15 cc blood only will be taken at two visits: pre-vaccination and post-vaccination (6 weeks). Serum will be separated, aliquoted and stored frozen at -20°C until analysis. The serum samples will be stored and tested in the TASMC Laboratory for Arthritis Research. VZV antibody
measure: Tender and Swollen Joint Count (28 joint count)
time frame: 6 weeks
description: Twenty-eight (28) joints will be assessed by a physician to determine the number of joints that are considered tender/painful. The response to pressure/motion on each joint will be assessed using the following scale: Present/Absent/Not Done/Not Applicable (to be used for artificial joints). These joints will be further assessed for swelling using the same scale.
The 28 joints to be assessed are the shoulders, elbows, wrists, metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, and knees. Artificial joints will not be assessed.
measure: Patient Assessment of Arthritis Pain
time frame: 6 weeks
description: Participants will assess the severity of their arthritis pain using a 100 mm visual analog scale (VAS) placing a mark on the scale between 0 (no pain) and 100 (most severe pain), which corresponds to the magnitude of their pain.
measure: Patient Global Assessment of Arthritis
time frame: 6 weeks
description: Participants will answer the following question, "Considering all the ways your arthritis affects you, how are you feeling today?" The subject's response will be recorded using a 100 mm VAS
measure: Physician Global Assessment of Arthritis
time frame: 6 weeks
description: The physician will assess how the subject's overall arthritis appears at the time of the visit. This is an evaluation based on the subject's disease signs, functional capacity and physical examination, and should be independent of the Patient's Global Assessment of Arthritis. The Investigator's response will be recorded using a 100 mm VAS.
measure: Health Assessment Questionnaire - Disability Index (HAQ-DI)
time frame: 6 weeks
description: The HAQ-DI assesses the degree of difficulty a subject has experienced during the past week in 8 domains of daily living activities: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other activities.13 Each activity category consists of 2-3 items. For each question in the questionnaire, the level of difficulty is scored from 0 to 3 with 0 representing "no difficulty," 1 as "some difficulty," 2 as "much difficulty," and 3 as "unable to do". Any activity that requires assistance from another individual or requires the use of an assistive device adjusts to a minimum score of 2 to represent a more limited functional status. The form should then be checked by the site staff for completeness.
arm group label: RA patients
arm group type: Experimental
description: RA patients will be administered Zostavax vaccine once 2 weeks before initiation of bDMARD, and be monitored accordingly
arm group label: Healthy Controls
arm group type: Experimental
description: healthy control patients will be administered Zostavax vaccine and be monitored accordingly
intervention type: Biological
intervention name: Zostavax vaccine
description: After the screening, the eligible patients who provided the informed consent, will be administered the zoster vaccine.
arm group label: Healthy Controls
arm group label: RA patients
other name: ZOSTAVAX® (Zoster Vaccine Live)
criteria: 
gender: All
minimum age: 50 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
facility: 
facility: 
facility: 
country: Israel
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PMID: 18050184
citation: Schmajuk G, Trivedi AN, Solomon DH, Yelin E, Trupin L, Chakravarty EF, Yazdany J. Receipt of disease-modifying antirheumatic drugs among patients with rheumatoid arthritis in Medicare managed care plans. JAMA. 2011 Feb 2;305(5):480-6. doi: 10.1001/jama.2011.67.
PMID: 21285425
citation: Widdifield J, Bernatsky S, Paterson JM, Gunraj N, Thorne JC, Pope J, Cividino A, Bombardier C. Serious infections in a population-based cohort of 86,039 seniors with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2013 Mar;65(3):353-61. doi: 10.1002/acr.21812.
PMID: 22833532
citation: Yun H, Yang S, Chen L, Xie F, Winthrop K, Baddley JW, Saag KG, Singh J, Curtis JR. Risk of Herpes Zoster in Autoimmune and Inflammatory Diseases: Implications for Vaccination. Arthritis Rheumatol. 2016 Sep;68(9):2328-37. doi: 10.1002/art.39670.
PMID: 26990731
citation: Strangfeld A, Listing J, Herzer P, Liebhaber A, Rockwitz K, Richter C, Zink A. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA. 2009 Feb 18;301(7):737-44. doi: 10.1001/jama.2009.146.
PMID: 19224750
citation: Curtis JR, Xie F, Yun H, Bernatsky S, Winthrop KL. Real-world comparative risks of herpes virus infections in tofacitinib and biologic-treated patients with rheumatoid arthritis. Ann Rheum Dis. 2016 Oct;75(10):1843-7. doi: 10.1136/annrheumdis-2016-209131. Epub 2016 Apr 25.
PMID: 27113415
citation: Schmader KE, Levin MJ, Gnann JW Jr, McNeil SA, Vesikari T, Betts RF, Keay S, Stek JE, Bundick ND, Su SC, Zhao Y, Li X, Chan IS, Annunziato PW, Parrino J. Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50-59 years. Clin Infect Dis. 2012 Apr;54(7):922-8. doi: 10.1093/cid/cir970. Epub 2012 Jan 30.
PMID: 22291101
citation: Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, Arbeit RD, Simberkoff MS, Gershon AA, Davis LE, Weinberg A, Boardman KD, Williams HM, Zhang JH, Peduzzi PN, Beisel CE, Morrison VA, Guatelli JC, Brooks PA, Kauffman CA, Pachucki CT, Neuzil KM, Betts RF, Wright PF, Griffin MR, Brunell P, Soto NE, Marques AR, Keay SK, Goodman RP, Cotton DJ, Gnann JW Jr, Loutit J, Holodniy M, Keitel WA, Crawford GE, Yeh SS, Lobo Z, Toney JF, Greenberg RN, Keller PM, Harbecke R, Hayward AR, Irwin MR, Kyriakides TC, Chan CY, Chan IS, Wang WW, Annunziato PW, Silber JL; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005 Jun 2;352(22):2271-84. doi: 10.1056/NEJMoa051016.
PMID: 15930418
citation: Calabrese LH, Calabrese C, Kirchner E. The 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis Should Include New Standards for Hepatitis B Screening: Comment on the Article by Singh et al. Arthritis Care Res (Hoboken). 2016 May;68(5):723-4. doi: 10.1002/acr.22865. No abstract available.
PMID: 26866816
citation: Yun H, Xie F, Delzell E, Chen L, Levitan EB, Lewis JD, Saag KG, Beukelman T, Winthrop K, Baddley JW, Curtis JR. Risks of herpes zoster in patients with rheumatoid arthritis according to biologic disease-modifying therapy. Arthritis Care Res (Hoboken). 2015 May;67(5):731-6. doi: 10.1002/acr.22470.
PMID: 25201241
citation: Koshima I, Higaki H, Soeda S. Combined vascularized fibula and peroneal composite-flap transfer for severe heat-press injury of the forearm. Plast Reconstr Surg. 1991 Aug;88(2):338-41. doi: 10.1097/00006534-199108000-00030.
PMID: 1852831
citation: Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, Moreland LW, O'Dell J, Winthrop KL, Beukelman T, Bridges SL Jr, Chatham WW, Paulus HE, Suarez-Almazor M, Bombardier C, Dougados M, Khanna D, King CM, Leong AL, Matteson EL, Schousboe JT, Moynihan E, Kolba KS, Jain A, Volkmann ER, Agrawal H, Bae S, Mudano AS, Patkar NM, Saag KG. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012 May;64(5):625-39. doi: 10.1002/acr.21641. No abstract available.
PMID: 22473917
citation: Russell AF, Parrino J, Fisher CL Jr, Spieler W, Stek JE, Coll KE, Su SC, Xu J, Li X, Schlienger K, Silber JL. Safety, tolerability, and immunogenicity of zoster vaccine in subjects on chronic/maintenance corticosteroids. Vaccine. 2015 Jun 17;33(27):3129-34. doi: 10.1016/j.vaccine.2015.04.090. Epub 2015 May 8.
PMID: 25964168
responsible party type: Sponsor
mesh term: Herpes Simplex
mesh term: Herpes Zoster
mesh term: Vaccines
sharing ipd: No