<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/NCT03815578</url>
  </required_header>
  <id_info>
    <org_study_id>CHUBX 2017/39</org_study_id>
    <nct_id>NCT03815578</nct_id>
  </id_info>
  <brief_title>Evaluation of Pain Sensitization in Rheumatoid Arthritis: Analysis on a Cohort of Tofacitinib Treated Patients</brief_title>
  <acronym>TOPRA</acronym>
  <official_title>Evaluation of Pain Sensitization in Rheumatoid Arthritis: Analysis on a Cohort of Tofacitinib Treated Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Bordeaux</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Bordeaux</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>
      Persistent pain and chronic fatigue are very common complaints in rheumatoid arthritis (RA)&#xD;
      patients, whatever the anti-inflammatory treatment response. Interestingly, pain remaining&#xD;
      despite good clinical response was associated with high disability and low inflammation at&#xD;
      baseline, suggesting a mechanism of pain independent of inflammation in these patients. Such&#xD;
      patients, with discordantly high patient-reported DAS28 components, fatigue and mood&#xD;
      disturbance might represent a subgroup of RA patients who have specific clinical needs, not&#xD;
      resolved by classical conventional or biologic DMARDs. In this way, neuropathic pain and pain&#xD;
      sensitization have been demonstrated in 20 to 30% of RA patients, neuropathic pain scores&#xD;
      being associated with worsen disease activity scores. Thus, pain sensitization may contribute&#xD;
      to amplification of pain in active RA, and should be responsible for persisting pain and&#xD;
      fatigue even after inflammation has resolved.&#xD;
&#xD;
      Pain sensitization is associated with neuroplastic changes in sensory pathways at peripheral&#xD;
      and central levels. Interestingly, major mediators responsible for this neuroplasticity&#xD;
      operate via a JAK/STAT signaling pathway, which is specifically targeted by new RA&#xD;
      treatments. New drug targeting JAK/STAT signalling pathway have been recently designed for RA&#xD;
      treatment, based on the implication of this pathway on the signaling of various cytokines&#xD;
      implicated in the pathophysiology of RA, such as IL-6, IL-12, IL-23 and IFNs. Two&#xD;
      Jak-inhibitors have been put on the market: Tofacitinib and Baricitinib. In randomized&#xD;
      clinical trials, Tofacitinib have shown a remarkable efficacy on pain and other patient&#xD;
      reported outcomes, suggesting a specific effect or jak-inhibitors on pain control. Recent&#xD;
      data suggest that Jak-inhibitors could have a direct effect on sensory neurons.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 17, 2019</start_date>
  <completion_date type="Actual">April 28, 2023</completion_date>
  <primary_completion_date type="Actual">April 28, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Variation of the mean Pressure Pain Thresholds (PPTs)</measure>
    <time_frame>At 6 months from baseline</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Variation of Mechanical Temporal Summation (MTS)</measure>
    <time_frame>At 1, 3 and 6 months from baseline</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Variation of Pressure Pain Thresholds (PPTs)</measure>
    <time_frame>At 1, 3 and 6 months from baseline</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Variation of Diffuse noxious inhibitory control (DNIC) values</measure>
    <time_frame>At 1, 3 and 6 months from baseline</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Variation of Daily joint pain intensity</measure>
    <time_frame>At 1, 3 and 6 months from baseline</time_frame>
    <description>daily evaluation of the previous 24h pain on a numeric pain scale 0 to 100</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease activity evaluated by the Disease Activity Score on 28 joints (DAS28)</measure>
    <time_frame>At 1, 3 and 6 months from baseline</time_frame>
    <description>which take into account the number of painful joints (on 28 joints), the number of swollen joints (on 28 joints), the patient global assessment of disease activity (between 0 and 100), and the erythrocyte sedimentation rate.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease activity evaluated by the Simple Disease Activity Index (SDAI)</measure>
    <time_frame>At 1, 3 and 6 months from baseline</time_frame>
    <description>which take into account the number of painful joints (on 28 joints), the number of swollen joints (on 28 joints), the patient global assessment of disease activity (between 0 and 100), the physician global assessment of disease activity (between 0 and 100), and the C-reactive protein level.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease activity evaluated by the Clinical Disease Activity Index (SDAI)</measure>
    <time_frame>At 1, 3 and 6 months from baseline</time_frame>
    <description>which take into account the number of painful joints (on 28 joints), the number of swollen joints (on 28 joints), the patient global assessment of disease activity (between 0 and 100), and the physician global assessment of disease activity (between 0 and 100).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health Assessment Questionnaire (HAQ)</measure>
    <time_frame>At 1, 3 and 6 months from baseline</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rheumatoid Arthritis Impact of Disease score (RAID)</measure>
    <time_frame>At 1, 3 and 6 months from baseline</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital Anxiety and Depression scale</measure>
    <time_frame>At 1, 3 and 6 months from baseline</time_frame>
    <description>HAD scale aims at evaluating anxiety and depression symptoms with two separate scores (between 0 and 21) estimated grace to 14 items (7 for anxiety and 7 for depression) ranged between 0 and 3</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Coping Strategy Questionnaire: a 21-items self-report</measure>
    <time_frame>At 1, 3 and 6 months from baseline</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of cytokines</measure>
    <time_frame>At 3 and 6 months from baseline</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of neurotrophins</measure>
    <time_frame>At 3 and 6 months from baseline</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of miR21, miR-124, miR-146a and miR-155</measure>
    <time_frame>At 3 and 6 months from baseline</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Rheumatoid Arthritis</condition>
  <arm_group>
    <arm_group_label>Rheumatoid Arthritis (RA) patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>RA according to the ACR/EULAR 2010 classification criteria</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Clinical examination</intervention_name>
    <description>Number of painful joints,&#xD;
Number of swollen joints,&#xD;
Patient Global assessment VAS (0 - 100)&#xD;
and Physician Global assessment VAS (0 - 100)</description>
    <arm_group_label>Rheumatoid Arthritis (RA) patients</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Pain assessment</intervention_name>
    <description>Pressure Pain Thresholds (PPTs),&#xD;
Mechanical Temporal Summation (MTS)&#xD;
and Diffuse Noxious Inhibitory Control (DNIC)</description>
    <arm_group_label>Rheumatoid Arthritis (RA) patients</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>blood sample</intervention_name>
    <description>18 ml whole blood for ELISA analysis and miRNAs detection</description>
    <arm_group_label>Rheumatoid Arthritis (RA) patients</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Patient Reported Outcomes</intervention_name>
    <description>Health Assessment Questionnaire (HAQ),&#xD;
Rheumatoid Arthritis Impact of Disease score (RAID),&#xD;
Daily joint pain intensity VAS (0-100),&#xD;
Hospital Anxiety and Depression scale&#xD;
and Coping Strategy Questionnaire.</description>
    <arm_group_label>Rheumatoid Arthritis (RA) patients</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients aged over 18 year-old ;&#xD;
&#xD;
          -  Diagnosis of RA according to the ACR/EULAR 2010 classification criteria ;&#xD;
&#xD;
          -  Active rheumatoid arthritis defined by a Disease Activity Score (DAS28) &gt; 3.2 at&#xD;
             inclusion ;&#xD;
&#xD;
          -  Patient eligible for tofacitinib treatment in agreement with European treatment&#xD;
             labelling and French recommendation for RA treatment ;&#xD;
&#xD;
          -  Oral prednisone intake is allowed until 10 mg, stable for at least 1 week at study&#xD;
             entry ;&#xD;
&#xD;
          -  Starting tofacitinib treatment for an active RA defined by a DAS28-ESR &gt; 3.2 ;&#xD;
&#xD;
          -  Affiliated person or beneficiary of a social security scheme ;&#xD;
&#xD;
          -  Having signed an informed consent (at the latest on the day of inclusion and before&#xD;
             any examination required by research).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of a systemic autoimmune disease other than RA ;&#xD;
&#xD;
          -  Peripheral neuropathy ;&#xD;
&#xD;
          -  Centrally-acting pain medications use within 3 months of enrolment (amitriptyline,&#xD;
             gabapentin, duloxetine), or during the study ;&#xD;
&#xD;
          -  Any opioid use within 1 month of enrolment or during the study ;&#xD;
&#xD;
          -  Corticosteroid treatment over 10 mg of prednisone or equivalent ;&#xD;
&#xD;
          -  Patient who present contraindications to tofacitinib treatment ;&#xD;
&#xD;
          -  Patient presenting with a history of active tuberculosis or chronic infectious disease&#xD;
             with a need of regular use of antibiotic ;&#xD;
&#xD;
          -  Patients with active bacterial or viral infection, or presenting with an episode of&#xD;
             infection that required treatment with antibiotics within 30 days prior to screening ;&#xD;
&#xD;
          -  Patient presenting with a history of lymphoma or leukaemia or other malignancy besides&#xD;
             non-melanoma skin cancer within 5 years ;&#xD;
&#xD;
          -  Patient presenting with any uncontrolled medical condition ;&#xD;
&#xD;
          -  Pregnancy or breast-feeding ;&#xD;
&#xD;
          -  Patient unable to understand and follow recommendations or unable to perform&#xD;
             self-evaluation ;&#xD;
&#xD;
          -  Patient who refuse to participate to the study.&#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>Thierry SCHAEVERBEKE, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>CHU Bordeaux</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>CHU de Bordeaux - Service de rhumatologie</name>
      <address>
        <city>Bordeaux</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Limoges - service de rhumatologie</name>
      <address>
        <city>Limoges</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>January 11, 2019</study_first_submitted>
  <study_first_submitted_qc>January 23, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 24, 2019</study_first_posted>
  <last_update_submitted>May 3, 2023</last_update_submitted>
  <last_update_submitted_qc>May 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>pain sensitization</keyword>
  <keyword>Tofacitinib</keyword>
  <keyword>miRNA</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>
  </condition_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/NCT03815578
org study id: CHUBX 2017/39
nct id: NCT03815578
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Persistent pain and chronic fatigue are very common complaints in rheumatoid arthritis (RA)
      patients, whatever the anti-inflammatory treatment response. Interestingly, pain remaining
      despite good clinical response was associated with high disability and low inflammation at
      baseline, suggesting a mechanism of pain independent of inflammation in these patients. Such
      patients, with discordantly high patient-reported DAS28 components, fatigue and mood
      disturbance might represent a subgroup of RA patients who have specific clinical needs, not
      resolved by classical conventional or biologic DMARDs. In this way, neuropathic pain and pain
      sensitization have been demonstrated in 20 to 30% of RA patients, neuropathic pain scores
      being associated with worsen disease activity scores. Thus, pain sensitization may contribute
      to amplification of pain in active RA, and should be responsible for persisting pain and
      fatigue even after inflammation has resolved.

      Pain sensitization is associated with neuroplastic changes in sensory pathways at peripheral
      and central levels. Interestingly, major mediators responsible for this neuroplasticity
      operate via a JAK/STAT signaling pathway, which is specifically targeted by new RA
      treatments. New drug targeting JAK/STAT signalling pathway have been recently designed for RA
      treatment, based on the implication of this pathway on the signaling of various cytokines
      implicated in the pathophysiology of RA, such as IL-6, IL-12, IL-23 and IFNs. Two
      Jak-inhibitors have been put on the market: Tofacitinib and Baricitinib. In randomized
      clinical trials, Tofacitinib have shown a remarkable efficacy on pain and other patient
      reported outcomes, suggesting a specific effect or jak-inhibitors on pain control. Recent
      data suggest that Jak-inhibitors could have a direct effect on sensory neurons.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Variation of the mean Pressure Pain Thresholds (PPTs)
time frame: At 6 months from baseline
measure: Variation of Mechanical Temporal Summation (MTS)
time frame: At 1, 3 and 6 months from baseline
measure: Variation of Pressure Pain Thresholds (PPTs)
time frame: At 1, 3 and 6 months from baseline
measure: Variation of Diffuse noxious inhibitory control (DNIC) values
time frame: At 1, 3 and 6 months from baseline
measure: Variation of Daily joint pain intensity
time frame: At 1, 3 and 6 months from baseline
description: daily evaluation of the previous 24h pain on a numeric pain scale 0 to 100
measure: Disease activity evaluated by the Disease Activity Score on 28 joints (DAS28)
time frame: At 1, 3 and 6 months from baseline
description: which take into account the number of painful joints (on 28 joints), the number of swollen joints (on 28 joints), the patient global assessment of disease activity (between 0 and 100), and the erythrocyte sedimentation rate.
measure: Disease activity evaluated by the Simple Disease Activity Index (SDAI)
time frame: At 1, 3 and 6 months from baseline
description: which take into account the number of painful joints (on 28 joints), the number of swollen joints (on 28 joints), the patient global assessment of disease activity (between 0 and 100), the physician global assessment of disease activity (between 0 and 100), and the C-reactive protein level.
measure: Disease activity evaluated by the Clinical Disease Activity Index (SDAI)
time frame: At 1, 3 and 6 months from baseline
description: which take into account the number of painful joints (on 28 joints), the number of swollen joints (on 28 joints), the patient global assessment of disease activity (between 0 and 100), and the physician global assessment of disease activity (between 0 and 100).
measure: Health Assessment Questionnaire (HAQ)
time frame: At 1, 3 and 6 months from baseline
measure: Rheumatoid Arthritis Impact of Disease score (RAID)
time frame: At 1, 3 and 6 months from baseline
measure: Hospital Anxiety and Depression scale
time frame: At 1, 3 and 6 months from baseline
description: HAD scale aims at evaluating anxiety and depression symptoms with two separate scores (between 0 and 21) estimated grace to 14 items (7 for anxiety and 7 for depression) ranged between 0 and 3
measure: Coping Strategy Questionnaire: a 21-items self-report
time frame: At 1, 3 and 6 months from baseline
measure: Levels of cytokines
time frame: At 3 and 6 months from baseline
measure: Levels of neurotrophins
time frame: At 3 and 6 months from baseline
measure: Levels of miR21, miR-124, miR-146a and miR-155
time frame: At 3 and 6 months from baseline
arm group label: Rheumatoid Arthritis (RA) patients
arm group type: Experimental
description: RA according to the ACR/EULAR 2010 classification criteria
intervention type: Other
intervention name: Clinical examination
description: Number of painful joints,
Number of swollen joints,
Patient Global assessment VAS (0 - 100)
and Physician Global assessment VAS (0 - 100)
arm group label: Rheumatoid Arthritis (RA) patients
intervention type: Other
intervention name: Pain assessment
description: Pressure Pain Thresholds (PPTs),
Mechanical Temporal Summation (MTS)
and Diffuse Noxious Inhibitory Control (DNIC)
arm group label: Rheumatoid Arthritis (RA) patients
intervention type: Other
intervention name: blood sample
description: 18 ml whole blood for ELISA analysis and miRNAs detection
arm group label: Rheumatoid Arthritis (RA) patients
intervention type: Other
intervention name: Patient Reported Outcomes
description: Health Assessment Questionnaire (HAQ),
Rheumatoid Arthritis Impact of Disease score (RAID),
Daily joint pain intensity VAS (0-100),
Hospital Anxiety and Depression scale
and Coping Strategy Questionnaire.
arm group label: Rheumatoid Arthritis (RA) patients
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Thierry SCHAEVERBEKE, Prof
role: Principal Investigator
affiliation: CHU Bordeaux
facility: 
facility: 
country: France
responsible party type: Sponsor
mesh term: Arthritis
mesh term: Arthritis, Rheumatoid
sharing ipd: No