<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/NCT03267147</url>
  </required_header>
  <id_info>
    <org_study_id>TMP-1016_01</org_study_id>
    <nct_id>NCT03267147</nct_id>
  </id_info>
  <brief_title>PREVALENCE OF Anti-CCP POSITIVITY AND SUBCLINICAL SIGNS OF INFLAMMATION IN PATIENTS WITH NEW ONSET OF NON-SPECIFIC MUSCULOSKELETAL SYMPTOMS</brief_title>
  <acronym>PANORA</acronym>
  <official_title>PREVALENCE OF ANTI-CYCLIC CITRULLINATED PEPTIDE (Anti-CCP) POSITIVITY AND SUBCLINICAL SIGNS OF INFLAMMATION IN PATIENTS WITH NEW ONSET OF NON-SPECIFIC MUSCULOSKELETAL SYMPTOMS POSSIBLY RELATED TO EARLY RHEUMATOID ARTHRITIS IN GENERAL PRACTICES IN GERMANY</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fraunhofer Institute for Molecular Biology and Applied Ecology</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Goethe University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Fraunhofer Institute for Molecular Biology and Applied Ecology</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Non-interventional, prospective, observational study to assess the relative risk of anti-CCP&#xD;
      positive patients to develop (subclinical) signs of inflammation in accordance with early&#xD;
      Rheumatoid Arthritis (RA) in a population without pre-classified RA but new1 onset of&#xD;
      non-specific musculoskeletal (MSK) symptoms in general practices in Germany and subsequent 36&#xD;
      months follow-up by rheumatologists&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Studies of early arthritis cohorts have shown that a large number of early arthritis patients&#xD;
      cannot be accurately diagnosed at their first visit, and hence are often referred as&#xD;
      undifferentiated arthritis patients. If patients are found to be anti-CCP(+) when referred to&#xD;
      the clinician, however, more than 90% develop RA within 3 years - in contrast to only 30% of&#xD;
      the anti-CCP(-) patients. The presence of anti-CCP antibodies in undifferentiated arthritis&#xD;
      therefore accurately predicts development of RA. Anti-CCP antibodies are very specific for&#xD;
      RA, and they are produced at significant level very early in disease. The specificity of&#xD;
      anti-CCP antibodies for the diagnosis of RA is high (94.1-99.0%). Moreover, it has been&#xD;
      reported that anti-CCP antibodies can be present many years before the first visit to the&#xD;
      clinic (up to 18 years). Furthermore, the presence of anti-CCP antibodies at the first visit&#xD;
      to the clinician predicts radiographic progression, as demonstrated by many studies that have&#xD;
      shown a strong association of anti-CCP positivity with the development of bone erosions.Early&#xD;
      diagnosis of RA coupled with rational use of disease-modifying anti-rheumatic drugs (DMARD)&#xD;
      has been shown to have a favourable effect on the course of the disease. Early and accurate&#xD;
      diagnosis has therefore become increasingly important. Implementing anti-CCP quick tests in&#xD;
      general practices could facilitate an early detection of RA or the allocation to a high risk&#xD;
      RA group. This, in turn, would guarantee an early referral of the patient to a rheumatologist&#xD;
      and together with other clinical examinations can aid in the early diagnosis and treatment.&#xD;
      As has been shown in many studies an early intervention is vital to preserve joint function&#xD;
      and to improve patient care. In this study, we want to assess the relative risk for patients&#xD;
      derived from GPs in Germany with new onset of non-specific MSK symptoms and anti-CCP test&#xD;
      positivity to develop (subclinical) signs of inflammation in accordance with early RA. Those&#xD;
      patients will be identified in general practices and will be tested for anti-CCP status.&#xD;
      Anti-CCP positive patients will then be introduced to a rheumatologist to validate anti-CCP&#xD;
      status and examine presence of clinical signs of early RA in addition to subclinical signs of&#xD;
      MSK inflammation. Furthermore, to focus on the possibility of early detection of anti-CCP&#xD;
      before the onset of clinically active arthritis, patients will be followed-up by a&#xD;
      rheumatologist until detection of early RA or up to 36 months in total. Early RA will be&#xD;
      examined using standard of care for signs of inflammation including clinical examination for&#xD;
      swollen and tender joints. In addition, ultrasound will be performed to assess joint&#xD;
      inflammation as well as fluorescence optical imaging technique (Xiralite®) to sensitively&#xD;
      illustrate changes in microvascularisation as a marker of subclinical inflammation. In cases&#xD;
      of RA diagnosis, the study ends with the date of diagnosis and patients will receive&#xD;
      treatment according to local guidelines earlier and medical care will be continued in&#xD;
      clinical routine care conditions outside of the study. Moreover, the cooperation status&#xD;
      between GPs and rheumatologists will be evaluated using qualitative interviews. Feasibility&#xD;
      of the diagnosis of early RA in at risk patients as well as the feasibility of the&#xD;
      transferral of these patients from the general practice to the rheumatologist will be&#xD;
      assessed. Training of GPs for detection of early RA will be improved. Overall, the hypothesis&#xD;
      of the study is that patients with new onset of unspecific MSK-symptoms and who are positive&#xD;
      for anti-CCP, which both are risk factors for developing RA, will be earlier introduced to&#xD;
      and monitored by a rheumatologist for proper clinical examination and potential treatment&#xD;
      when establishing RA, which in turn will not only improve patient care, disease outcomes and&#xD;
      quality of life, but might also be cost effective.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 27, 2017</start_date>
  <completion_date type="Actual">February 15, 2022</completion_date>
  <primary_completion_date type="Actual">December 16, 2021</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>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Determination of the relative risk in patients with new onset of non-specific MSK symptoms who are anti-CCP positive to develop (subclinical) signs of inflammation in accordance with early RA in general practices in Germany</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
    <description>Determination if RA symptoms are present</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>diagnosis of RA in the group of anti-CCP positive patients with new onset of non-specific MSK symptoms</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>subclinical signs of inflammation using routine examination methods in anti-CCP positive patients</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>subclinical signs of inflammation using fluorescence optical imaging technique in anti-CCP positive patients</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>subclinical signs of inflammation using ultrasound in anti-CCP positive patients</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>anti-CCP level over time in anti-CCP positive patients</measure>
    <time_frame>over 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EQ5D</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
    <description>Questionnaire to assess Quality of Life profile of anti-CCP positive patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>SF36</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
    <description>Questionnaire to assess Quality of Life profile of anti-CCP positive patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HAQ</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
    <description>Questionnaire to assess disability profile of anti-CCP positive patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PHQ-9</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
    <description>Questionnaire to assess depression profile of anti-CCP positive patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>WPAI</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
    <description>Questionnaire to assess work ability profile of anti-CCP positive patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>assessment of time to disease in anti-CCP positive patients</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>assessment of correlation of anti-CCP level in anti-CCP positive patients</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>assessment quality of life (QoL) in anti-CCP positive patients</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>assessment work ability profile in anti-CCP positive patients</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>assessment subclinical signs of inflammation in anti-CCP positive patients</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>assessment risk of depression in anti-CCP positive patients</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>assessment of grade of disability in anti-CCP positive patients</measure>
    <time_frame>every 6 months up to 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>diagnosis of RA in the group of ELISA test anti-CCP negative patients with new onset of non-specific MSK symptoms</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>diagnosis of RA in the group of ELISA test anti-CCP negative patients with new onset of non-specific MSK symptoms</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>diagnosis of RA in the group of quick test anti-CCP negative patients with new onset of non-specific MSK symptoms</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Qualitative assessment of general practitioners' (GP) routine care</measure>
    <time_frame>1 year</time_frame>
    <description>qualitative interviews with the GP to evaluate current status of how patients with MSK symptoms are treated/forwarded in general practices</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">986</enrollment>
  <condition>Rheumatoid Arthritis</condition>
  <arm_group>
    <arm_group_label>antiCCP positive</arm_group_label>
    <description>Patients with a positive result in the anti-CCP quick test and positive in antiCCP ELISA will be examined by Rheumatologist for detection of RA symptoms and followed-up for 3 years or until RA diagnosis&#xD;
no intervention is given</description>
  </arm_group>
  <arm_group>
    <arm_group_label>antiCCP negative</arm_group_label>
    <description>Patient with negative result in antiCCP quick test or negative antiCCP ELISA will be followed-up after one year (and 3 years for ELISA negative patients) with a short questionnaire if musculoskeletal symptoms are still present or if RA was diagnosed</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>no intervention is given</intervention_name>
    <description>no intervention is given</description>
    <arm_group_label>antiCCP negative</arm_group_label>
    <arm_group_label>antiCCP positive</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      blood samples&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        population without pre-classified RA but new onset of non-specific musculoskeletal (MSK)&#xD;
        symptoms&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  New onset of non-specific MSK symptoms, including, but not limited to, arthralgia of&#xD;
             the hands and the large joints such as wrists, knees, and shoulders&#xD;
&#xD;
          -  Written informed consent obtained prior to the initiation of any study&#xD;
             protocol-required procedures&#xD;
&#xD;
          -  General understanding of study procedure and informed consent&#xD;
&#xD;
          -  Age ≥ 18 and ≤ 65 years&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  RA diagnosed according to modified EULAR/ACR (american college of&#xD;
             rheumatology)-criteria&#xD;
&#xD;
          -  Other known arthritis&#xD;
&#xD;
          -  Other known reasons for MSK symptoms, e.g. mechanical, traumatic, etc.&#xD;
&#xD;
          -  MSK symptoms previously reported at another (general) practice&#xD;
&#xD;
          -  Alcohol, drug or chemical abuse&#xD;
&#xD;
          -  Underage or incapable patients&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Frank Behrens, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fraunhofer IME</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>CIRI</name>
      <address>
        <city>Frankfurt am Main</city>
        <state>Hessia</state>
        <zip>60596</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>July 4, 2017</study_first_submitted>
  <study_first_submitted_qc>August 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 30, 2017</study_first_posted>
  <last_update_submitted>March 1, 2022</last_update_submitted>
  <last_update_submitted_qc>March 1, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 2, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Fraunhofer Institute for Molecular Biology and Applied Ecology</investigator_affiliation>
    <investigator_full_name>Dr. Frank Behrens</investigator_full_name>
    <investigator_title>Head of clinical research department</investigator_title>
  </responsible_party>
  <keyword>Anti-CCP</keyword>
  <keyword>rheumatoid arthritis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Arthritis</mesh_term>
    <mesh_term>Arthritis, Rheumatoid</mesh_term>
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03267147
org study id: TMP-1016_01
nct id: NCT03267147
lead sponsor: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
Non-interventional, prospective, observational study to assess the relative risk of anti-CCP
      positive patients to develop (subclinical) signs of inflammation in accordance with early
      Rheumatoid Arthritis (RA) in a population without pre-classified RA but new1 onset of
      non-specific musculoskeletal (MSK) symptoms in general practices in Germany and subsequent 36
      months follow-up by rheumatologists
Studies of early arthritis cohorts have shown that a large number of early arthritis patients
      cannot be accurately diagnosed at their first visit, and hence are often referred as
      undifferentiated arthritis patients. If patients are found to be anti-CCP(+) when referred to
      the clinician, however, more than 90% develop RA within 3 years - in contrast to only 30% of
      the anti-CCP(-) patients. The presence of anti-CCP antibodies in undifferentiated arthritis
      therefore accurately predicts development of RA. Anti-CCP antibodies are very specific for
      RA, and they are produced at significant level very early in disease. The specificity of
      anti-CCP antibodies for the diagnosis of RA is high (94.1-99.0%). Moreover, it has been
      reported that anti-CCP antibodies can be present many years before the first visit to the
      clinic (up to 18 years). Furthermore, the presence of anti-CCP antibodies at the first visit
      to the clinician predicts radiographic progression, as demonstrated by many studies that have
      shown a strong association of anti-CCP positivity with the development of bone erosions.Early
      diagnosis of RA coupled with rational use of disease-modifying anti-rheumatic drugs (DMARD)
      has been shown to have a favourable effect on the course of the disease. Early and accurate
      diagnosis has therefore become increasingly important. Implementing anti-CCP quick tests in
      general practices could facilitate an early detection of RA or the allocation to a high risk
      RA group. This, in turn, would guarantee an early referral of the patient to a rheumatologist
      and together with other clinical examinations can aid in the early diagnosis and treatment.
      As has been shown in many studies an early intervention is vital to preserve joint function
      and to improve patient care. In this study, we want to assess the relative risk for patients
      derived from GPs in Germany with new onset of non-specific MSK symptoms and anti-CCP test
      positivity to develop (subclinical) signs of inflammation in accordance with early RA. Those
      patients will be identified in general practices and will be tested for anti-CCP status.
      Anti-CCP positive patients will then be introduced to a rheumatologist to validate anti-CCP
      status and examine presence of clinical signs of early RA in addition to subclinical signs of
      MSK inflammation. Furthermore, to focus on the possibility of early detection of anti-CCP
      before the onset of clinically active arthritis, patients will be followed-up by a
      rheumatologist until detection of early RA or up to 36 months in total. Early RA will be
      examined using standard of care for signs of inflammation including clinical examination for
      swollen and tender joints. In addition, ultrasound will be performed to assess joint
      inflammation as well as fluorescence optical imaging technique (Xiralite®) to sensitively
      illustrate changes in microvascularisation as a marker of subclinical inflammation. In cases
      of RA diagnosis, the study ends with the date of diagnosis and patients will receive
      treatment according to local guidelines earlier and medical care will be continued in
      clinical routine care conditions outside of the study. Moreover, the cooperation status
      between GPs and rheumatologists will be evaluated using qualitative interviews. Feasibility
      of the diagnosis of early RA in at risk patients as well as the feasibility of the
      transferral of these patients from the general practice to the rheumatologist will be
      assessed. Training of GPs for detection of early RA will be improved. Overall, the hypothesis
      of the study is that patients with new onset of unspecific MSK-symptoms and who are positive
      for anti-CCP, which both are risk factors for developing RA, will be earlier introduced to
      and monitored by a rheumatologist for proper clinical examination and potential treatment
      when establishing RA, which in turn will not only improve patient care, disease outcomes and
      quality of life, but might also be cost effective.
observational model: Cohort
time perspective: Prospective
measure: Determination of the relative risk in patients with new onset of non-specific MSK symptoms who are anti-CCP positive to develop (subclinical) signs of inflammation in accordance with early RA in general practices in Germany
time frame: every 6 months up to 3 years
description: Determination if RA symptoms are present
measure: diagnosis of RA in the group of anti-CCP positive patients with new onset of non-specific MSK symptoms
time frame: every 6 months up to 3 years
measure: subclinical signs of inflammation using routine examination methods in anti-CCP positive patients
time frame: every 6 months up to 3 years
measure: subclinical signs of inflammation using fluorescence optical imaging technique in anti-CCP positive patients
time frame: every 6 months up to 3 years
measure: subclinical signs of inflammation using ultrasound in anti-CCP positive patients
time frame: every 6 months up to 3 years
measure: anti-CCP level over time in anti-CCP positive patients
time frame: over 3 years
measure: EQ5D
time frame: every 6 months up to 3 years
description: Questionnaire to assess Quality of Life profile of anti-CCP positive patients
measure: SF36
time frame: every 6 months up to 3 years
description: Questionnaire to assess Quality of Life profile of anti-CCP positive patients
measure: HAQ
time frame: every 6 months up to 3 years
description: Questionnaire to assess disability profile of anti-CCP positive patients
measure: PHQ-9
time frame: every 6 months up to 3 years
description: Questionnaire to assess depression profile of anti-CCP positive patients
measure: WPAI
time frame: every 6 months up to 3 years
description: Questionnaire to assess work ability profile of anti-CCP positive patients
measure: assessment of time to disease in anti-CCP positive patients
time frame: every 6 months up to 3 years
measure: assessment of correlation of anti-CCP level in anti-CCP positive patients
time frame: every 6 months up to 3 years
measure: assessment quality of life (QoL) in anti-CCP positive patients
time frame: every 6 months up to 3 years
measure: assessment work ability profile in anti-CCP positive patients
time frame: every 6 months up to 3 years
measure: assessment subclinical signs of inflammation in anti-CCP positive patients
time frame: every 6 months up to 3 years
measure: assessment risk of depression in anti-CCP positive patients
time frame: every 6 months up to 3 years
measure: assessment of grade of disability in anti-CCP positive patients
time frame: every 6 months up to 3 years
measure: diagnosis of RA in the group of ELISA test anti-CCP negative patients with new onset of non-specific MSK symptoms
time frame: 1 year
measure: diagnosis of RA in the group of ELISA test anti-CCP negative patients with new onset of non-specific MSK symptoms
time frame: 3 years
measure: diagnosis of RA in the group of quick test anti-CCP negative patients with new onset of non-specific MSK symptoms
time frame: 1 year
measure: Qualitative assessment of general practitioners' (GP) routine care
time frame: 1 year
description: qualitative interviews with the GP to evaluate current status of how patients with MSK symptoms are treated/forwarded in general practices
arm group label: antiCCP positive
description: Patients with a positive result in the anti-CCP quick test and positive in antiCCP ELISA will be examined by Rheumatologist for detection of RA symptoms and followed-up for 3 years or until RA diagnosis
no intervention is given
arm group label: antiCCP negative
description: Patient with negative result in antiCCP quick test or negative antiCCP ELISA will be followed-up after one year (and 3 years for ELISA negative patients) with a short questionnaire if musculoskeletal symptoms are still present or if RA was diagnosed
intervention type: Other
intervention name: no intervention is given
description: no intervention is given
arm group label: antiCCP negative
arm group label: antiCCP positive
blood samples
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Frank Behrens, MD
role: Principal Investigator
affiliation: Fraunhofer IME
facility: 
country: Germany
responsible party type: Principal Investigator
investigator affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology
investigator full name: Dr. Frank Behrens
investigator title: Head of clinical research department
mesh term: Arthritis
mesh term: Arthritis, Rheumatoid
mesh term: Inflammation
sharing ipd: Undecided