<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/NCT02196480</url>
  </required_header>
  <id_info>
    <org_study_id>PPV23JIA-aTNF</org_study_id>
    <nct_id>NCT02196480</nct_id>
  </id_info>
  <brief_title>23-valent Polysaccharide Pneumococcal Vaccine in Juvenile Idiopathic Arthritis Patients Under Anti-TNF Therapy</brief_title>
  <official_title>Short and Long-term Immunogenicity and Safety Following the 23-valent Polysaccharide Pneumococcal Vaccine in Juvenile Idiopathic Arthritis Patients Under Anti-TNF Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Sao Paulo</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Sao Paulo</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Objectives: To assess immunogenicity and safety of the 23-valent polysaccharide pneumococcal&#xD;
      vaccine (PPV23) in JIA patients with and without anti-TNF therapy. The influences of&#xD;
      demographic data, disease activity and treatment on immune response and the potential&#xD;
      deleterious effect of vaccine on disease itself were also evaluated.&#xD;
&#xD;
      Methods: 17 JIA patients immediately pre-etanercept (Group 1) and 10 JIA patients on stable&#xD;
      dose of methotrexate (Group 2) will receive one dose of PPV23. All patients will be evaluated&#xD;
      pre-vaccination, 2 months and 12 months post-vaccination for seven pneumoccocal serotypes.&#xD;
      Serology will be performed by enzyme immunoassay and the immunogenicity endpoints will&#xD;
      include seroprotection (SP), seroconversion (SP) and geometric mean concentration of&#xD;
      antibodies (GMC). Clinical and laboratorial parameters of JIA will be evaluated before and&#xD;
      after vaccination.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Seventeen JIA patients (International League Against Rheumatism criteria) followed at the&#xD;
      Pediatric Rheumatology Unit of Children's Institute of Hospital das Clínicas da Faculdade de&#xD;
      Medicina da Universidade de São Paulo and who are refractory to methotrexate [median dose 0.9&#xD;
      mg/kg/week (0.7 - 1)] will be included immediately before the association of anti-TNF&#xD;
      (etanercept 0.8 mg/kg/week, Group 1) to the previous therapy. The control group (Group 2)&#xD;
      consist of 10 JIA patients on stable dose of methotrexate [median dose 0.8 mg/kg/week&#xD;
      (0.3-1.0)]. One intramuscular dose of PPV23 (Sanofi Pasteur), lot B0381-3, at the&#xD;
      immunization center of the same hospital will be given to each study subject.&#xD;
&#xD;
      Participants are ≥ 5 and ≤ 18 years old and patients with previous vaccination against S.&#xD;
      pneumoniae will be excluded. This study was approved by the Local Ethical Committee of our&#xD;
      University Hospital and an informed consent was obtained from all participants or their legal&#xD;
      guardians.&#xD;
&#xD;
      Vaccine immunogenicity Blood samples will be collected pre-vaccination, 2 months and 12&#xD;
      months post-vaccination for 7 pneumoccocal serotypes (4, 6B, 9V, 14, 18C, 19F, 23F). Samples&#xD;
      will be centrifuged and serum will be frozen and stored at -70 ◦C until tested. In order to&#xD;
      eliminate non-specific antibodies that may exhibit cross-reactivity, the samples will be&#xD;
      pre-absorbed with the C-polysaccharide and with the heterologous serotype 22F.&#xD;
&#xD;
      Serology for each serotype will be performed by enzyme immunoassay and immunogenicity&#xD;
      endpoints will include seroprotection rate (SP) (percentage of subjects achieving antibodies&#xD;
      titers ≥1.3 micrograms/mL), seroconversion rate (SC) (percentage of subjects with a minimum&#xD;
      of 2-fold rise in post-vaccination antibodies titers) and the geometric mean concentration of&#xD;
      antibodies (GMC). Adequate vaccine response will be considered when SC occur for at least 50%&#xD;
      of all seven vaccine serotypes.&#xD;
&#xD;
      During the period of one year after PPV23 vaccination, all upper and lower respiratory tract&#xD;
      infections will be weekly recorded during clinical appointments.&#xD;
&#xD;
      Safety: The number of participants with local and systemic adverse events will be assessed as&#xD;
      a measure of safety and tolerability. Local reactions were considered to be related to the&#xD;
      PPV23, while systemic adverse events were analyzed individually to determine their causality.&#xD;
      Severe adverse events were defined as those requiring hospitalization or death.&#xD;
&#xD;
      Clinical, laboratorial and therapy assessment: All patients will be evaluated on the day of&#xD;
      vaccination, 2 months and 12 months after immunization for clinical and laboratorial&#xD;
      parameters: number of active joints (swelling within a joint, or limitation in the range of&#xD;
      joint movement with joint pain or tenderness), number of limited joints, morning stiffness,&#xD;
      patient and physician global assessment of arthritis activity measured with pain scores on&#xD;
      the Visual Analog Scale&quot; (VAS) and validated Brazilian version of Childhood Health Assessment&#xD;
      Questionnaire (CHAQ). Erythrocyte sedimentation rate (ESR) was evaluated according to&#xD;
      Westergreen method and C-reactive protein (CRP) according to nephelometry. The Juvenile&#xD;
      Arthritis Disease Activity Score with 27-joint reduced count (JADAS-27), defined as the&#xD;
      linear sum of the scores of 4 components [physician global assessment of disease activity&#xD;
      (measured on a 10-cm VAS), parent/patient global assessment of well-being (measured on a&#xD;
      10-cm VAS); number of active joints (0-27 joints); and ESR] (range: 0 - 57 points), will be&#xD;
      calculated in all JIA patients. Current concomitant treatment with non-steroidal&#xD;
      anti-inflammatory drug, prednisone, methotrexate, leflunomide and cyclosporine will be&#xD;
      evaluated.&#xD;
&#xD;
      Statistical analysis: Immunogenicity and safety analyses will be descriptive and data will be&#xD;
      presented as number (%) or median (range). The GMCs will be compared between JIA patients&#xD;
      with and without anti-TNF therapy using a two-sided Student's t-test or Mann-Whitney U-test&#xD;
      on the log10-transformed titers. The prospective analysis of GMCs for each of seven&#xD;
      pneumococcal serotypes will be performed by Friedman Repeated Measures ANOVA on Ranks.&#xD;
      Categorical variables (rates of seroprotection and seroconversion, prednisone and&#xD;
      immunosuppressive drugs use) will be compared using Fisher's exact test. The prospective&#xD;
      analysis of seroprotection and seroconversion rates for each of seven pneumococcal serotypes&#xD;
      will be performed by McNemar's Test. The effects before and after vaccination on disease&#xD;
      activity will be analyzed with the Wilcoxon signed ranks test. The statistical significance&#xD;
      was set at p value &lt; 0.05.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2008</start_date>
  <completion_date type="Actual">June 2012</completion_date>
  <primary_completion_date type="Actual">June 2011</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>Seroprotection rate</measure>
    <time_frame>2 months after vacccination</time_frame>
    <description>Sseroprotection rate (SP): percentage of subjects achieving antibodies titers ≥1.3 micrograms/mL</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Seroconversion rate</measure>
    <time_frame>2 months after vaccination</time_frame>
    <description>Seroconversion rate (SC): percentage of subjects with a minimum of 2-fold rise in post-vaccination antibodies titers</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with local and systemic adverse events</measure>
    <time_frame>Until 12 months</time_frame>
    <description>Local reactions were considered to be related to the PPV23, while systemic adverse events were analyzed individually to determine their causality. Severe adverse events were defined as those requiring hospitalization or death.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Seroprotection rate</measure>
    <time_frame>12 months after vaccination</time_frame>
    <description>Seroprotection rate (SP): percentage of subjects achieving antibodies titers ≥1.3 micrograms/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Seroconversion rate</measure>
    <time_frame>12 months after vaccination</time_frame>
    <description>Seroconversion rate (SC): percentage of subjects with a minimum of 2-fold rise in post-vaccination antibodies titers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Juvenile Arthritis Disease Activity Score with 27-joint reduced count (JADAS-27)</measure>
    <time_frame>2 months after vaccination</time_frame>
    <description>The Juvenile Arthritis Disease Activity Score with 27-joint reduced count (JADAS-27) is defined as the linear sum of the scores of 4 components [physician global assessment of disease activity (measured on a 10-cm VAS), parent/patient global assessment of well-being (measured on a 10-cm VAS); number of active joints (0-27 joints); and ESR] (range: 0 - 57 points)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Juvenile Arthritis Disease Activity Score with 27-joint reduced count (JADAS-27)</measure>
    <time_frame>12 months after vaccination</time_frame>
    <description>The Juvenile Arthritis Disease Activity Score with 27-joint reduced count (JADAS-27) is defined as the linear sum of the scores of 4 components [physician global assessment of disease activity (measured on a 10-cm VAS), parent/patient global assessment of well-being (measured on a 10-cm VAS); number of active joints (0-27 joints); and ESR] (range: 0 - 57 points)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">27</enrollment>
  <condition>Juvenile Idiopathic Arthritis</condition>
  <arm_group>
    <arm_group_label>Methotrexate</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>JIA patients on stable dose of methotrexate vaccinated with PPV23</description>
  </arm_group>
  <arm_group>
    <arm_group_label>anti-TNF</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>JIA patients refractory to methotrexate immediately before the association of anti-TNF vaccinated with PPV23</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>anti-TNF</intervention_name>
    <description>Anti-tumor necrosis factor therapy</description>
    <arm_group_label>anti-TNF</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Juvenile idiopathic arthritis criteria (International League Against Rheumatism&#xD;
             criteria)&#xD;
&#xD;
          -  ≥ 5 and ≤ 18 years old&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous vaccination against S. pneumoniae&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>5 Years</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nadia E Aikawa, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Sao Paulo</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Centro de Dispensação de Medicamentos de Alto Custo (CEDMAC)</name>
      <address>
        <city>Sao Paulo</city>
        <zip>01246-903</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <verification_date>July 2014</verification_date>
  <study_first_submitted>July 16, 2014</study_first_submitted>
  <study_first_submitted_qc>July 18, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 22, 2014</study_first_posted>
  <last_update_submitted>July 18, 2014</last_update_submitted>
  <last_update_submitted_qc>July 18, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 22, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Sao Paulo</investigator_affiliation>
    <investigator_full_name>Nádia Emi Aikawa</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Arthritis</mesh_term>
    <mesh_term>Arthritis, Juvenile</mesh_term>
  </condition_browse>
  <!-- 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/NCT02196480
org study id: PPV23JIA-aTNF
nct id: NCT02196480
lead sponsor: 
has dmc: No
Objectives: To assess immunogenicity and safety of the 23-valent polysaccharide pneumococcal
      vaccine (PPV23) in JIA patients with and without anti-TNF therapy. The influences of
      demographic data, disease activity and treatment on immune response and the potential
      deleterious effect of vaccine on disease itself were also evaluated.

      Methods: 17 JIA patients immediately pre-etanercept (Group 1) and 10 JIA patients on stable
      dose of methotrexate (Group 2) will receive one dose of PPV23. All patients will be evaluated
      pre-vaccination, 2 months and 12 months post-vaccination for seven pneumoccocal serotypes.
      Serology will be performed by enzyme immunoassay and the immunogenicity endpoints will
      include seroprotection (SP), seroconversion (SP) and geometric mean concentration of
      antibodies (GMC). Clinical and laboratorial parameters of JIA will be evaluated before and
      after vaccination.
Seventeen JIA patients (International League Against Rheumatism criteria) followed at the
      Pediatric Rheumatology Unit of Children's Institute of Hospital das Clínicas da Faculdade de
      Medicina da Universidade de São Paulo and who are refractory to methotrexate [median dose 0.9
      mg/kg/week (0.7 - 1)] will be included immediately before the association of anti-TNF
      (etanercept 0.8 mg/kg/week, Group 1) to the previous therapy. The control group (Group 2)
      consist of 10 JIA patients on stable dose of methotrexate [median dose 0.8 mg/kg/week
      (0.3-1.0)]. One intramuscular dose of PPV23 (Sanofi Pasteur), lot B0381-3, at the
      immunization center of the same hospital will be given to each study subject.

      Participants are ≥ 5 and ≤ 18 years old and patients with previous vaccination against S.
      pneumoniae will be excluded. This study was approved by the Local Ethical Committee of our
      University Hospital and an informed consent was obtained from all participants or their legal
      guardians.

      Vaccine immunogenicity Blood samples will be collected pre-vaccination, 2 months and 12
      months post-vaccination for 7 pneumoccocal serotypes (4, 6B, 9V, 14, 18C, 19F, 23F). Samples
      will be centrifuged and serum will be frozen and stored at -70 ◦C until tested. In order to
      eliminate non-specific antibodies that may exhibit cross-reactivity, the samples will be
      pre-absorbed with the C-polysaccharide and with the heterologous serotype 22F.

      Serology for each serotype will be performed by enzyme immunoassay and immunogenicity
      endpoints will include seroprotection rate (SP) (percentage of subjects achieving antibodies
      titers ≥1.3 micrograms/mL), seroconversion rate (SC) (percentage of subjects with a minimum
      of 2-fold rise in post-vaccination antibodies titers) and the geometric mean concentration of
      antibodies (GMC). Adequate vaccine response will be considered when SC occur for at least 50%
      of all seven vaccine serotypes.

      During the period of one year after PPV23 vaccination, all upper and lower respiratory tract
      infections will be weekly recorded during clinical appointments.

      Safety: The number of participants with local and systemic adverse events will be assessed as
      a measure of safety and tolerability. Local reactions were considered to be related to the
      PPV23, while systemic adverse events were analyzed individually to determine their causality.
      Severe adverse events were defined as those requiring hospitalization or death.

      Clinical, laboratorial and therapy assessment: All patients will be evaluated on the day of
      vaccination, 2 months and 12 months after immunization for clinical and laboratorial
      parameters: number of active joints (swelling within a joint, or limitation in the range of
      joint movement with joint pain or tenderness), number of limited joints, morning stiffness,
      patient and physician global assessment of arthritis activity measured with pain scores on
      the Visual Analog Scale" (VAS) and validated Brazilian version of Childhood Health Assessment
      Questionnaire (CHAQ). Erythrocyte sedimentation rate (ESR) was evaluated according to
      Westergreen method and C-reactive protein (CRP) according to nephelometry. The Juvenile
      Arthritis Disease Activity Score with 27-joint reduced count (JADAS-27), defined as the
      linear sum of the scores of 4 components [physician global assessment of disease activity
      (measured on a 10-cm VAS), parent/patient global assessment of well-being (measured on a
      10-cm VAS); number of active joints (0-27 joints); and ESR] (range: 0 - 57 points), will be
      calculated in all JIA patients. Current concomitant treatment with non-steroidal
      anti-inflammatory drug, prednisone, methotrexate, leflunomide and cyclosporine will be
      evaluated.

      Statistical analysis: Immunogenicity and safety analyses will be descriptive and data will be
      presented as number (%) or median (range). The GMCs will be compared between JIA patients
      with and without anti-TNF therapy using a two-sided Student's t-test or Mann-Whitney U-test
      on the log10-transformed titers. The prospective analysis of GMCs for each of seven
      pneumococcal serotypes will be performed by Friedman Repeated Measures ANOVA on Ranks.
      Categorical variables (rates of seroprotection and seroconversion, prednisone and
      immunosuppressive drugs use) will be compared using Fisher's exact test. The prospective
      analysis of seroprotection and seroconversion rates for each of seven pneumococcal serotypes
      will be performed by McNemar's Test. The effects before and after vaccination on disease
      activity will be analyzed with the Wilcoxon signed ranks test. The statistical significance
      was set at p value < 0.05.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Seroprotection rate
time frame: 2 months after vacccination
description: Sseroprotection rate (SP): percentage of subjects achieving antibodies titers ≥1.3 micrograms/mL
measure: Seroconversion rate
time frame: 2 months after vaccination
description: Seroconversion rate (SC): percentage of subjects with a minimum of 2-fold rise in post-vaccination antibodies titers
measure: Number of participants with local and systemic adverse events
time frame: Until 12 months
description: Local reactions were considered to be related to the PPV23, while systemic adverse events were analyzed individually to determine their causality. Severe adverse events were defined as those requiring hospitalization or death.
measure: Seroprotection rate
time frame: 12 months after vaccination
description: Seroprotection rate (SP): percentage of subjects achieving antibodies titers ≥1.3 micrograms/mL
measure: Seroconversion rate
time frame: 12 months after vaccination
description: Seroconversion rate (SC): percentage of subjects with a minimum of 2-fold rise in post-vaccination antibodies titers
measure: Juvenile Arthritis Disease Activity Score with 27-joint reduced count (JADAS-27)
time frame: 2 months after vaccination
description: The Juvenile Arthritis Disease Activity Score with 27-joint reduced count (JADAS-27) is defined as the linear sum of the scores of 4 components [physician global assessment of disease activity (measured on a 10-cm VAS), parent/patient global assessment of well-being (measured on a 10-cm VAS); number of active joints (0-27 joints); and ESR] (range: 0 - 57 points)
measure: Juvenile Arthritis Disease Activity Score with 27-joint reduced count (JADAS-27)
time frame: 12 months after vaccination
description: The Juvenile Arthritis Disease Activity Score with 27-joint reduced count (JADAS-27) is defined as the linear sum of the scores of 4 components [physician global assessment of disease activity (measured on a 10-cm VAS), parent/patient global assessment of well-being (measured on a 10-cm VAS); number of active joints (0-27 joints); and ESR] (range: 0 - 57 points)
arm group label: Methotrexate
arm group type: No Intervention
description: JIA patients on stable dose of methotrexate vaccinated with PPV23
arm group label: anti-TNF
arm group type: Experimental
description: JIA patients refractory to methotrexate immediately before the association of anti-TNF vaccinated with PPV23
intervention type: Biological
intervention name: anti-TNF
description: Anti-tumor necrosis factor therapy
arm group label: anti-TNF
criteria: 
gender: All
minimum age: 5 Years
maximum age: 18 Years
healthy volunteers: No
last name: Nadia E Aikawa, MD, PhD
role: Principal Investigator
affiliation: University of Sao Paulo
facility: 
country: Brazil
responsible party type: Principal Investigator
investigator affiliation: University of Sao Paulo
investigator full name: Nádia Emi Aikawa
investigator title: MD, PhD
mesh term: Arthritis
mesh term: Arthritis, Juvenile