<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/NCT04407559</url>
  </required_header>
  <id_info>
    <org_study_id>RECHMPL20_0330</org_study_id>
    <nct_id>NCT04407559</nct_id>
  </id_info>
  <brief_title>COVID-SErology in Rheumatoid Arthritis (COVID-19)</brief_title>
  <acronym>COVID-SERA</acronym>
  <official_title>Impact of the Rheumatoid Factor on Serological Testing Performance for Covid-19 in Rheumatoid Arthritis Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Montpellier</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital, Montpellier</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Due to the Covid-19 worldwide outbreak, fragile patients with immune diseases, notably&#xD;
      rheumatoid arthritis (RA), have to be even more specifically and carefully followed-up.&#xD;
      However, it has been shown that false postive serological results often occured while&#xD;
      detecting antibodies directed against SARS-CoV-2 in patients with positive rheumatodoid&#xD;
      factor (RF). The investigators propose here to investigated this issue. Therefore, the&#xD;
      investigators will test three different immunoassays on this specific population. The&#xD;
      investigators aim to establish these assays specificity and the levels of RF for which there&#xD;
      is a risk of anti-SARS-CoV-2 false positivity and thus ensure a better follow-up of RA&#xD;
      patients. The RF isotype will be analysed to determine whether there is a correlation and the&#xD;
      impact of the presence of anti-CCP (citrullinated cyclic antipeptide antibodies) will be&#xD;
      studied and assessed.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rheumatoid arthritis (RA) is the most common inflammatory rheumatism, affecting 0.5% to 1% of&#xD;
      the European population. Characterized by symmetrical and distal erosive polyarthritis, its&#xD;
      diagnosis is based on the association of the clinical assessment combined with the presence&#xD;
      of a chronic biological inflammatory syndrome and of citrullinated cyclic antipeptide&#xD;
      antibodies (CCP) and / or of rheumatoid factor. From a prognostic point of view, some factors&#xD;
      allow the risk prediction of the progression to structural damage (bone erosion), such as the&#xD;
      positivity of the rheumatoid factor or anti-CCP antibodies, and require the rapid&#xD;
      introduction of basic immunosuppressive therapy or biotherapy. In the context of the&#xD;
      SARS-CoV-2 pandemic, responsible for the COVID-19 disease, the interest of a serological test&#xD;
      is essential from an epidemiological point of view in order to follow the evolution of the&#xD;
      pandemic, and to adapt the strategy of de-confinement of the general population or of&#xD;
      patients at risk. However, RA patients receiving biotherapy present an increased risk of&#xD;
      infection. In this context of de-confinement, a SARS-CoV-2 serological analysis, before&#xD;
      initiating RA patients future treatment or in order to adapt their current treatment, would&#xD;
      be useful.&#xD;
&#xD;
      Detection of antibodies directed against SARS-CoV-2 by various detection kits is currently&#xD;
      under evaluation. To the lack of serological test kits on the French market is added the&#xD;
      complexity of verifying the sensitivity and specificity of these tests. On the other hand,&#xD;
      the immune response to SARS-CoV-2 is complex and still quite unknown. The concomitant&#xD;
      presence of several isotypes IgA, IgM and IgG is frequently observed. Thus, the isotypic&#xD;
      switching of Ig does not seem to take place correctly in this disease case, which randers the&#xD;
      serodiagnostics even more complicated to implement. Detection of the less specific IgMs would&#xD;
      therefore be essential, in the case of SARS-CoV-2. Rheumatoid factor (RF) is an&#xD;
      immunoglobulin (Ig), more often of the M type, directed against the Fc fragment of IgG. This&#xD;
      antibody, although not directly pathogenic, is very frequently present in RA patients (70 to&#xD;
      80%), without being specific for this pathology since it can be observed in other autoimmune,&#xD;
      infectious or hematological diseases as well. The presence of RF IgM, all the more in high&#xD;
      titers, is problematic while performing many serological or immunological assays since these&#xD;
      high levels can be responsible for false positive results.&#xD;
&#xD;
      During previous SARS epidemics (SARS-CoV-1 or MERS-CoV), false positive results of&#xD;
      serological tests were observed. When detecting anti-SARS-CoV-1 IgG or IgM in patients who&#xD;
      had not contracted SARS, the use of an ELISA kit, with plates coated with a cell lysate of&#xD;
      Vero-E6 cells infected with SARS-CoV-1, had been shown to induce a low number of false&#xD;
      positive results in healthy controls (less than 5%). However, the number of false positive&#xD;
      results in patients with autoimmune diseases was much higher, and varied accordingly with the&#xD;
      pathology (between 10% and 58%), the largest number of false positive results being obtained&#xD;
      in lupus patients. This phenomenon can be explained by the use of an immune test using&#xD;
      unpurified cell lysates, which contain antigens against which the autoantibodies present in&#xD;
      the patient serum could react, thus distorting the outcome of the test. Other causes of&#xD;
      increase in the false positive results rate have been described when performing SARS-CoV-1&#xD;
      serologies, such as the presence of active neoplasia, or because of a previous infection with&#xD;
      another coronavirus. Indeed, other coronaviruses, such as HCoV-OC43 and HCoV-229E, display a&#xD;
      nucleocapsid close to the one of SARS-CoV-1 : this similarity can be the source of&#xD;
      cross-reactivity. The same phenomenon was observed with the latest coronavirus: it was&#xD;
      therefore suggested to rather use recombinant antigens of SARS-CoV-2 in immunoassays, such as&#xD;
      ELISA for instance Given the similarity between SARS-CoV1 and SARS-CoV2, it is likely that&#xD;
      the various elements causing false positive results during serological tests for SARS-CoV-1,&#xD;
      in particular the presence of auto-antibodies including RF, could also cause false positive&#xD;
      results when performing serological tests targeting SARS-CoV-2. A recent Chinese study showed&#xD;
      that a moderate or high rate of RF was associated with a significant rate of false positive&#xD;
      results when searching for anti-SARS-CoV-2 IgM with a ELISA kit, which plates were however&#xD;
      coated with recombinant antigen. The authors therefore proposed to include a urea&#xD;
      dissociation step into the ELISA protocol, which seemed to improve the specificity of the&#xD;
      test, without altering its sensitivity.&#xD;
&#xD;
      It thus appears essential to assess the influence of RF, for its different isotypes (IgG,&#xD;
      IgM, IgA), on various serological tests for SARS-CoV-2 available in France, in order to&#xD;
      better assess these tests specificity.&#xD;
&#xD;
      The investigators propose to evaluate and compare 3 different serological tests available for&#xD;
      the detection of specific SARS-CoV-2 IgG and IgM. The rate of false positive results obtained&#xD;
      for each type of test will be evaluated on sera originated from patients with RA who have&#xD;
      never been in contact with SARS-CoV-2, since these sera were withdrawn before July 2019. The&#xD;
      relation between the incidence of SARS-Cov-2 serological assays false positive results and RF&#xD;
      antibody levels could be estimated, as well as the characterization of RF.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 1, 2020</start_date>
  <completion_date type="Actual">September 30, 2020</completion_date>
  <primary_completion_date type="Actual">September 1, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Evaluate the false positive results rate</measure>
    <time_frame>4 months</time_frame>
    <description>Evaluate the false positive results rate when using each one of the three SARS-CoV-2 serology tests in patients with rheumatoid factor plasma levels, so as to define the specificity of these tests in this RA population. all serum samples will be tested by the 3 different immunoassays. The RF plasma levels have already been measured (routine exam) and are written in the patients files. The results will be analysed, the data proceeded and hopefully we will be able to answer the question.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Characterize the RF isotype (IgG, IgM or IgA) associated</measure>
    <time_frame>4 months</time_frame>
    <description>Characterize the RF isotype (IgG, IgM or IgA) associated with the false positivity of the test.all serum samples will be tested by the 3 different immunoassays. The RF isotype will be established using the routine method and the results of anti-CCP and RF plasma levels are already known and this information is available in the patients files. The results will be analysed, the data proceeded and hopefully we will be able to answer the questions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determine the influence of RA on the false positivity rate in subjects</measure>
    <time_frame>4 months</time_frame>
    <description>Determine the influence of RA on the false positivity rate in subjects with negative RF titer. All serum samples will be tested by the 3 different immunoassays. The RF isotype will be established using the routine method and the results of anti-CCP and RF plasma levels are already known and this information is available in the patients files. The results will be analysed, the data proceeded and hopefully we will be able to answer the questions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess the influence of the presence of anti-CCP on the false positivity of the SARS-CoV-2 test</measure>
    <time_frame>4 months</time_frame>
    <description>Assess the influence of the presence of anti-CCP on the false positivity of the SARS-CoV-2 test : all serum samples will be tested by the 3 different immunoassays. The RF isotype will be established using the routine method and the results of anti-CCP and RF plasma levels are already known and this information is available in the patients files. The results will be analysed, the data proceeded and hopefully we will be able to answer the questions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess the relation between the RF plasma levels and the false positivity of the SARS-CoV-2 test</measure>
    <time_frame>4 months</time_frame>
    <description>Assess the relation between the RF plasma levels and the false positivity of the SARS-CoV-2 test : all serum samples will be tested by the 3 different immunoassays. The RF isotype will be established using the routine method and the results of anti-CCP and RF plasma levels are already known and this information is available in the patients files. The results will be analysed, the data proceeded and hopefully we will be able to answer the questions.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">216</enrollment>
  <condition>COVID-19</condition>
  <condition>Rheumatoid Arthritis</condition>
  <arm_group>
    <arm_group_label>Groupe 1</arm_group_label>
    <description>Group 1: Rheumatoid arthritis seropositive for RF (+)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Groupe 2</arm_group_label>
    <description>Group 2: Rheumatoid arthritis seronegative for RF (-)</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Serological analyses to be lead on a pre-existing biobank</intervention_name>
    <description>3 immunoassays will be used according to the procedure described (Demey-2020; Tuaillon-2020) :&#xD;
WuHan UNscience Biotechnology Co., Ltd (Chine). COVID-19 IgG/IgM Rapid Test Kit, (Wuhan, China), will be refered as UNscience&#xD;
Chongqing iSIA BIO-Technology Co., Ltd (Chine). 2019-nCoV IgM/IgG Diagnostic Test Kit ; (Chongqing, China), will be refered as iSIA&#xD;
Xiamen Biotime Biotechnology Co. Ldt (Chine). (SARS-CoV-2) IgM/IgG Rapid Qualitative Test Kit, will be refered as Biotime.</description>
    <arm_group_label>Groupe 1</arm_group_label>
    <arm_group_label>Groupe 2</arm_group_label>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Frozen serum samples&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with rheumatoid arthritis (RA) Patients monitored at Montpellier University&#xD;
        Hospital Patients having an available and frozen serum sample withdrawn before July 2019&#xD;
        Patients over 18 years old&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
        - Samples from a pre-July 2019 RA patient biobank to ensure true negativity of Covid -19&#xD;
        (patients over 18 years old)&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
        - Patients who have traveled to China or Saudi Arabia and therefore may have encountered&#xD;
        other coronaviruses.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Rosanna FERREIRA, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UH Montpellier</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Uhmontpellier</name>
      <address>
        <city>Montpellier</city>
        <zip>34295</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>December 2020</verification_date>
  <study_first_submitted>May 27, 2020</study_first_submitted>
  <study_first_submitted_qc>May 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 29, 2020</study_first_posted>
  <last_update_submitted>December 28, 2020</last_update_submitted>
  <last_update_submitted_qc>December 28, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 29, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Arthritis</mesh_term>
    <mesh_term>Arthritis, Rheumatoid</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>NC</ipd_description>
  </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/NCT04407559
org study id: RECHMPL20_0330
nct id: NCT04407559
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Due to the Covid-19 worldwide outbreak, fragile patients with immune diseases, notably
      rheumatoid arthritis (RA), have to be even more specifically and carefully followed-up.
      However, it has been shown that false postive serological results often occured while
      detecting antibodies directed against SARS-CoV-2 in patients with positive rheumatodoid
      factor (RF). The investigators propose here to investigated this issue. Therefore, the
      investigators will test three different immunoassays on this specific population. The
      investigators aim to establish these assays specificity and the levels of RF for which there
      is a risk of anti-SARS-CoV-2 false positivity and thus ensure a better follow-up of RA
      patients. The RF isotype will be analysed to determine whether there is a correlation and the
      impact of the presence of anti-CCP (citrullinated cyclic antipeptide antibodies) will be
      studied and assessed.
Rheumatoid arthritis (RA) is the most common inflammatory rheumatism, affecting 0.5% to 1% of
      the European population. Characterized by symmetrical and distal erosive polyarthritis, its
      diagnosis is based on the association of the clinical assessment combined with the presence
      of a chronic biological inflammatory syndrome and of citrullinated cyclic antipeptide
      antibodies (CCP) and / or of rheumatoid factor. From a prognostic point of view, some factors
      allow the risk prediction of the progression to structural damage (bone erosion), such as the
      positivity of the rheumatoid factor or anti-CCP antibodies, and require the rapid
      introduction of basic immunosuppressive therapy or biotherapy. In the context of the
      SARS-CoV-2 pandemic, responsible for the COVID-19 disease, the interest of a serological test
      is essential from an epidemiological point of view in order to follow the evolution of the
      pandemic, and to adapt the strategy of de-confinement of the general population or of
      patients at risk. However, RA patients receiving biotherapy present an increased risk of
      infection. In this context of de-confinement, a SARS-CoV-2 serological analysis, before
      initiating RA patients future treatment or in order to adapt their current treatment, would
      be useful.

      Detection of antibodies directed against SARS-CoV-2 by various detection kits is currently
      under evaluation. To the lack of serological test kits on the French market is added the
      complexity of verifying the sensitivity and specificity of these tests. On the other hand,
      the immune response to SARS-CoV-2 is complex and still quite unknown. The concomitant
      presence of several isotypes IgA, IgM and IgG is frequently observed. Thus, the isotypic
      switching of Ig does not seem to take place correctly in this disease case, which randers the
      serodiagnostics even more complicated to implement. Detection of the less specific IgMs would
      therefore be essential, in the case of SARS-CoV-2. Rheumatoid factor (RF) is an
      immunoglobulin (Ig), more often of the M type, directed against the Fc fragment of IgG. This
      antibody, although not directly pathogenic, is very frequently present in RA patients (70 to
      80%), without being specific for this pathology since it can be observed in other autoimmune,
      infectious or hematological diseases as well. The presence of RF IgM, all the more in high
      titers, is problematic while performing many serological or immunological assays since these
      high levels can be responsible for false positive results.

      During previous SARS epidemics (SARS-CoV-1 or MERS-CoV), false positive results of
      serological tests were observed. When detecting anti-SARS-CoV-1 IgG or IgM in patients who
      had not contracted SARS, the use of an ELISA kit, with plates coated with a cell lysate of
      Vero-E6 cells infected with SARS-CoV-1, had been shown to induce a low number of false
      positive results in healthy controls (less than 5%). However, the number of false positive
      results in patients with autoimmune diseases was much higher, and varied accordingly with the
      pathology (between 10% and 58%), the largest number of false positive results being obtained
      in lupus patients. This phenomenon can be explained by the use of an immune test using
      unpurified cell lysates, which contain antigens against which the autoantibodies present in
      the patient serum could react, thus distorting the outcome of the test. Other causes of
      increase in the false positive results rate have been described when performing SARS-CoV-1
      serologies, such as the presence of active neoplasia, or because of a previous infection with
      another coronavirus. Indeed, other coronaviruses, such as HCoV-OC43 and HCoV-229E, display a
      nucleocapsid close to the one of SARS-CoV-1 : this similarity can be the source of
      cross-reactivity. The same phenomenon was observed with the latest coronavirus: it was
      therefore suggested to rather use recombinant antigens of SARS-CoV-2 in immunoassays, such as
      ELISA for instance Given the similarity between SARS-CoV1 and SARS-CoV2, it is likely that
      the various elements causing false positive results during serological tests for SARS-CoV-1,
      in particular the presence of auto-antibodies including RF, could also cause false positive
      results when performing serological tests targeting SARS-CoV-2. A recent Chinese study showed
      that a moderate or high rate of RF was associated with a significant rate of false positive
      results when searching for anti-SARS-CoV-2 IgM with a ELISA kit, which plates were however
      coated with recombinant antigen. The authors therefore proposed to include a urea
      dissociation step into the ELISA protocol, which seemed to improve the specificity of the
      test, without altering its sensitivity.

      It thus appears essential to assess the influence of RF, for its different isotypes (IgG,
      IgM, IgA), on various serological tests for SARS-CoV-2 available in France, in order to
      better assess these tests specificity.

      The investigators propose to evaluate and compare 3 different serological tests available for
      the detection of specific SARS-CoV-2 IgG and IgM. The rate of false positive results obtained
      for each type of test will be evaluated on sera originated from patients with RA who have
      never been in contact with SARS-CoV-2, since these sera were withdrawn before July 2019. The
      relation between the incidence of SARS-Cov-2 serological assays false positive results and RF
      antibody levels could be estimated, as well as the characterization of RF.
observational model: Cohort
time perspective: Retrospective
measure: Evaluate the false positive results rate
time frame: 4 months
description: Evaluate the false positive results rate when using each one of the three SARS-CoV-2 serology tests in patients with rheumatoid factor plasma levels, so as to define the specificity of these tests in this RA population. all serum samples will be tested by the 3 different immunoassays. The RF plasma levels have already been measured (routine exam) and are written in the patients files. The results will be analysed, the data proceeded and hopefully we will be able to answer the question.
measure: Characterize the RF isotype (IgG, IgM or IgA) associated
time frame: 4 months
description: Characterize the RF isotype (IgG, IgM or IgA) associated with the false positivity of the test.all serum samples will be tested by the 3 different immunoassays. The RF isotype will be established using the routine method and the results of anti-CCP and RF plasma levels are already known and this information is available in the patients files. The results will be analysed, the data proceeded and hopefully we will be able to answer the questions
measure: Determine the influence of RA on the false positivity rate in subjects
time frame: 4 months
description: Determine the influence of RA on the false positivity rate in subjects with negative RF titer. All serum samples will be tested by the 3 different immunoassays. The RF isotype will be established using the routine method and the results of anti-CCP and RF plasma levels are already known and this information is available in the patients files. The results will be analysed, the data proceeded and hopefully we will be able to answer the questions
measure: Assess the influence of the presence of anti-CCP on the false positivity of the SARS-CoV-2 test
time frame: 4 months
description: Assess the influence of the presence of anti-CCP on the false positivity of the SARS-CoV-2 test : all serum samples will be tested by the 3 different immunoassays. The RF isotype will be established using the routine method and the results of anti-CCP and RF plasma levels are already known and this information is available in the patients files. The results will be analysed, the data proceeded and hopefully we will be able to answer the questions.
measure: Assess the relation between the RF plasma levels and the false positivity of the SARS-CoV-2 test
time frame: 4 months
description: Assess the relation between the RF plasma levels and the false positivity of the SARS-CoV-2 test : all serum samples will be tested by the 3 different immunoassays. The RF isotype will be established using the routine method and the results of anti-CCP and RF plasma levels are already known and this information is available in the patients files. The results will be analysed, the data proceeded and hopefully we will be able to answer the questions.
arm group label: Groupe 1
description: Group 1: Rheumatoid arthritis seropositive for RF (+)
arm group label: Groupe 2
description: Group 2: Rheumatoid arthritis seronegative for RF (-)
intervention type: Other
intervention name: Serological analyses to be lead on a pre-existing biobank
description: 3 immunoassays will be used according to the procedure described (Demey-2020; Tuaillon-2020) :
WuHan UNscience Biotechnology Co., Ltd (Chine). COVID-19 IgG/IgM Rapid Test Kit, (Wuhan, China), will be refered as UNscience
Chongqing iSIA BIO-Technology Co., Ltd (Chine). 2019-nCoV IgM/IgG Diagnostic Test Kit ; (Chongqing, China), will be refered as iSIA
Xiamen Biotime Biotechnology Co. Ldt (Chine). (SARS-CoV-2) IgM/IgG Rapid Qualitative Test Kit, will be refered as Biotime.
arm group label: Groupe 1
arm group label: Groupe 2
Frozen serum samples
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Rosanna FERREIRA, MD
role: Principal Investigator
affiliation: UH Montpellier
facility: 
country: France
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Arthritis
mesh term: Arthritis, Rheumatoid
sharing ipd: Undecided
ipd description: NC