<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/NCT03775824</url>
  </required_header>
  <id_info>
    <org_study_id>FART1</org_study_id>
    <nct_id>NCT03775824</nct_id>
  </id_info>
  <brief_title>Faecal Analyses in Rheumatoid Arthritis Therapy</brief_title>
  <acronym>FART</acronym>
  <official_title>Faecal Analyses in Rheumatoid Arthritis Therapy: An Prospective Observational Study of the Intestinal Microbiome in Patients With Rheumatoid Arthritis Receiving Immunosuppressive Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Region Skane</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Region Skane</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study evaluates the intestinal microbiome and disease activity in patients with&#xD;
      rheumatoid arthritis receiving immunosuppressive therapy. Patients will be analysed at two&#xD;
      time points in reference to two predefined primary endpoints:&#xD;
&#xD;
        -  Changes in intestinal microbiome&#xD;
&#xD;
        -  Response to therapy&#xD;
&#xD;
      The investigators want to evaluate if successful treatment of rheumatoid arthritis coincide&#xD;
      with specific changes in the gut flora.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Methotrexate (MTX) and tumor necrosis factor (TNF) -inhibitors are two efficient medications&#xD;
      for the treatment of rheumatoid arthritis. In a substantial number of cases however, these&#xD;
      medications remain ineffective. At present, the scientific community has limited&#xD;
      understanding of why some patients are resistant to these medications. The purpose of this&#xD;
      study is to understand if the gut flora may associate with treatment response.&#xD;
&#xD;
      Recent studies have associated rheumatoid arthritis with intestinal dysbiosis. Specifically,&#xD;
      the bacteria Prevotella copri, has been associated with this disease, an observation that has&#xD;
      been supported also by mechanistic studies. In patients receiving methotrexate, normalization&#xD;
      of dysbiosis has been associated with successful treatment.&#xD;
&#xD;
      This study is of observational character and integrated in the routine clinical care of&#xD;
      patients with rheumatoid arthritis at the Rheumatology Clinic, Skane University Hospital,&#xD;
      Lund, Sweden. Study participants are asked to deliver blood and fecal sampling at two&#xD;
      time-points together with clinical evaluation of disease activity. With an estimated&#xD;
      inclusion of 50 patients, at least 20 responders and 20 non-responders are expected to be&#xD;
      included and to be compared to each other.&#xD;
&#xD;
      If successful treatment response in rheumatoid arthritis is associated with specific&#xD;
      alterations of the gut flora, these results may guide future studies on the impact of&#xD;
      dysbiosis and probiotics on this disease.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 1, 2016</start_date>
  <completion_date type="Actual">June 1, 2019</completion_date>
  <primary_completion_date type="Actual">November 1, 2018</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>Intestinal gut flora in rheumatoid arthritis</measure>
    <time_frame>Analysis made at study start/baseline</time_frame>
    <description>Intestinal gut flora based on DNA-based microbial analysis of fecal samples</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in gut flora</measure>
    <time_frame>Change from baseline Dysbiosis Index Score at 6 months</time_frame>
    <description>Change in Dysbiosis Index Score at follow up compared to baseline.&#xD;
The Dysbiosis Index Score measures degree of intestinal dysbiosis on a scale from 1 to 5, where 5 indicates dysbiosis. The Index has been extensively described at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029765/</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in disease activity/treatment response at follow up</measure>
    <time_frame>Change from baseline DAS-28 at 6 months</time_frame>
    <description>Change in Disease Activity Score 28 (DAS-28), an established index of disease activity in rheumatoid arthritis between 0-10, where 10 equals maximum activity.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adherance to immunosuppressive therapy</measure>
    <time_frame>Analysis made at 6 months follow up</time_frame>
    <description>Is the patient still prescribed the same immunosuppressant compared to baseline?</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in intestinal concentration Prevotella</measure>
    <time_frame>Change from baseline concentration at 6 months</time_frame>
    <description>Alterations in intestinal concentrations of Prevotella bacteria according to polymerase chain reaction (PCR)-based analysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in intestinal concentration Lactobacillus</measure>
    <time_frame>Change from baseline concentration at 6 months</time_frame>
    <description>Alterations in intestinal concentrations of Lactobacillus bacteria according to PCR-based analysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in intestinal concentration Clostridia</measure>
    <time_frame>Change from baseline concentration at 6 months</time_frame>
    <description>Alterations in intestinal concentrations of Clostridia bacteria according to PCR-based analysis</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Rheumatoid Arthritis</condition>
  <arm_group>
    <arm_group_label>MTX start</arm_group_label>
    <description>Patients with active rheumatoid arthritis who are either naive to methotrexate, or have not used this medicine in the last year and who are about to start therapy with methotrexate i.v. or s.c.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>TNF start</arm_group_label>
    <description>Patients with active rheumatoid arthritis who are either naive to TNF-inhibitors, or have not used this medicine in the last year and who are about to start therapy with any of the following (biosimilars included); infliximab, adalimumab, etanercept, certolizumab or golimumab</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>MTX start</intervention_name>
    <description>Patient prescribed MTX s.c. or p.o. because of active rheumatoid arthritis</description>
    <arm_group_label>MTX start</arm_group_label>
    <other_name>MTX</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TNF start</intervention_name>
    <description>Patient prescribed TNF-inhibitor because of active rheumatoid arthritis</description>
    <arm_group_label>TNF start</arm_group_label>
    <other_name>TNF</other_name>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Faecal and blood samples from study participants are stored in a biorepository.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        This study encompasses consecutive patients with rheumatoid arthritis who by their&#xD;
        physician at the Rheumatology Clinic, Skåne University Hospital, have been prescribed any&#xD;
        of the predefined drugs.&#xD;
&#xD;
        Patients who are willing to comply with the study protocoll are included.&#xD;
&#xD;
        The study population is consequently not a sample, but encompasses a majority of patients&#xD;
        being prescribed theses medications at our University clinic.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Rheumatoid arthritis according to the 2010 classification criteria&#xD;
&#xD;
          -  About to start methotrexate or TNF-inhibitor because of active disease&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Failure to understand protocol&#xD;
&#xD;
          -  A history of alcohol abuse&#xD;
&#xD;
          -  Concomitant inflammatory bowel disease&#xD;
&#xD;
          -  Any history of diverticulitis&#xD;
&#xD;
          -  A history of failure to comply with prescribed medication&#xD;
&#xD;
          -  Ongoing biological therapy&#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>Kristofer Andréasson, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Skane University Hospital</affiliation>
  </overall_official>
  <reference>
    <citation>Andreasson K, Alrawi Z, Persson A, Jonsson G, Marsal J. Intestinal dysbiosis is common in systemic sclerosis and associated with gastrointestinal and extraintestinal features of disease. Arthritis Res Ther. 2016 Nov 29;18(1):278. doi: 10.1186/s13075-016-1182-z.</citation>
    <PMID>27894337</PMID>
  </reference>
  <reference>
    <citation>Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, Wu X, Li J, Tang L, Li Y, Lan Z, Chen B, Li Y, Zhong H, Xie H, Jie Z, Chen W, Tang S, Xu X, Wang X, Cai X, Liu S, Xia Y, Li J, Qiao X, Al-Aama JY, Chen H, Wang L, Wu QJ, Zhang F, Zheng W, Li Y, Zhang M, Luo G, Xue W, Xiao L, Li J, Chen W, Xu X, Yin Y, Yang H, Wang J, Kristiansen K, Liu L, Li T, Huang Q, Li Y, Wang J. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med. 2015 Aug;21(8):895-905. doi: 10.1038/nm.3914. Epub 2015 Jul 27.</citation>
    <PMID>26214836</PMID>
  </reference>
  <reference>
    <citation>Pianta A, Arvikar SL, Strle K, Drouin EE, Wang Q, Costello CE, Steere AC. Two rheumatoid arthritis-specific autoantigens correlate microbial immunity with autoimmune responses in joints. J Clin Invest. 2017 Aug 1;127(8):2946-2956. doi: 10.1172/JCI93450. Epub 2017 Jun 26.</citation>
    <PMID>28650341</PMID>
  </reference>
  <verification_date>September 2019</verification_date>
  <study_first_submitted>December 11, 2018</study_first_submitted>
  <study_first_submitted_qc>December 11, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 14, 2018</study_first_posted>
  <last_update_submitted>September 13, 2019</last_update_submitted>
  <last_update_submitted_qc>September 13, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">September 16, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Region Skane</investigator_affiliation>
    <investigator_full_name>Kristofer Andreasson</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <keyword>microbiome</keyword>
  <keyword>methotrexate</keyword>
  <keyword>tnf-inhibitor</keyword>
  <keyword>dysbiosis</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/NCT03775824
org study id: FART1
nct id: NCT03775824
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
This study evaluates the intestinal microbiome and disease activity in patients with
      rheumatoid arthritis receiving immunosuppressive therapy. Patients will be analysed at two
      time points in reference to two predefined primary endpoints:

        -  Changes in intestinal microbiome

        -  Response to therapy

      The investigators want to evaluate if successful treatment of rheumatoid arthritis coincide
      with specific changes in the gut flora.
Methotrexate (MTX) and tumor necrosis factor (TNF) -inhibitors are two efficient medications
      for the treatment of rheumatoid arthritis. In a substantial number of cases however, these
      medications remain ineffective. At present, the scientific community has limited
      understanding of why some patients are resistant to these medications. The purpose of this
      study is to understand if the gut flora may associate with treatment response.

      Recent studies have associated rheumatoid arthritis with intestinal dysbiosis. Specifically,
      the bacteria Prevotella copri, has been associated with this disease, an observation that has
      been supported also by mechanistic studies. In patients receiving methotrexate, normalization
      of dysbiosis has been associated with successful treatment.

      This study is of observational character and integrated in the routine clinical care of
      patients with rheumatoid arthritis at the Rheumatology Clinic, Skane University Hospital,
      Lund, Sweden. Study participants are asked to deliver blood and fecal sampling at two
      time-points together with clinical evaluation of disease activity. With an estimated
      inclusion of 50 patients, at least 20 responders and 20 non-responders are expected to be
      included and to be compared to each other.

      If successful treatment response in rheumatoid arthritis is associated with specific
      alterations of the gut flora, these results may guide future studies on the impact of
      dysbiosis and probiotics on this disease.
observational model: Cohort
time perspective: Prospective
measure: Intestinal gut flora in rheumatoid arthritis
time frame: Analysis made at study start/baseline
description: Intestinal gut flora based on DNA-based microbial analysis of fecal samples
measure: Change in gut flora
time frame: Change from baseline Dysbiosis Index Score at 6 months
description: Change in Dysbiosis Index Score at follow up compared to baseline.
The Dysbiosis Index Score measures degree of intestinal dysbiosis on a scale from 1 to 5, where 5 indicates dysbiosis. The Index has been extensively described at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029765/
measure: Change in disease activity/treatment response at follow up
time frame: Change from baseline DAS-28 at 6 months
description: Change in Disease Activity Score 28 (DAS-28), an established index of disease activity in rheumatoid arthritis between 0-10, where 10 equals maximum activity.
measure: Adherance to immunosuppressive therapy
time frame: Analysis made at 6 months follow up
description: Is the patient still prescribed the same immunosuppressant compared to baseline?
measure: Change in intestinal concentration Prevotella
time frame: Change from baseline concentration at 6 months
description: Alterations in intestinal concentrations of Prevotella bacteria according to polymerase chain reaction (PCR)-based analysis
measure: Change in intestinal concentration Lactobacillus
time frame: Change from baseline concentration at 6 months
description: Alterations in intestinal concentrations of Lactobacillus bacteria according to PCR-based analysis
measure: Change in intestinal concentration Clostridia
time frame: Change from baseline concentration at 6 months
description: Alterations in intestinal concentrations of Clostridia bacteria according to PCR-based analysis
arm group label: MTX start
description: Patients with active rheumatoid arthritis who are either naive to methotrexate, or have not used this medicine in the last year and who are about to start therapy with methotrexate i.v. or s.c.
arm group label: TNF start
description: Patients with active rheumatoid arthritis who are either naive to TNF-inhibitors, or have not used this medicine in the last year and who are about to start therapy with any of the following (biosimilars included); infliximab, adalimumab, etanercept, certolizumab or golimumab
intervention type: Drug
intervention name: MTX start
description: Patient prescribed MTX s.c. or p.o. because of active rheumatoid arthritis
arm group label: MTX start
other name: MTX
intervention type: Drug
intervention name: TNF start
description: Patient prescribed TNF-inhibitor because of active rheumatoid arthritis
arm group label: TNF start
other name: TNF
Faecal and blood samples from study participants are stored in a biorepository.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Kristofer Andréasson, MD PhD
role: Principal Investigator
affiliation: Skane University Hospital
citation: Andreasson K, Alrawi Z, Persson A, Jonsson G, Marsal J. Intestinal dysbiosis is common in systemic sclerosis and associated with gastrointestinal and extraintestinal features of disease. Arthritis Res Ther. 2016 Nov 29;18(1):278. doi: 10.1186/s13075-016-1182-z.
PMID: 27894337
citation: Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, Wu X, Li J, Tang L, Li Y, Lan Z, Chen B, Li Y, Zhong H, Xie H, Jie Z, Chen W, Tang S, Xu X, Wang X, Cai X, Liu S, Xia Y, Li J, Qiao X, Al-Aama JY, Chen H, Wang L, Wu QJ, Zhang F, Zheng W, Li Y, Zhang M, Luo G, Xue W, Xiao L, Li J, Chen W, Xu X, Yin Y, Yang H, Wang J, Kristiansen K, Liu L, Li T, Huang Q, Li Y, Wang J. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med. 2015 Aug;21(8):895-905. doi: 10.1038/nm.3914. Epub 2015 Jul 27.
PMID: 26214836
citation: Pianta A, Arvikar SL, Strle K, Drouin EE, Wang Q, Costello CE, Steere AC. Two rheumatoid arthritis-specific autoantigens correlate microbial immunity with autoimmune responses in joints. J Clin Invest. 2017 Aug 1;127(8):2946-2956. doi: 10.1172/JCI93450. Epub 2017 Jun 26.
PMID: 28650341
responsible party type: Principal Investigator
investigator affiliation: Region Skane
investigator full name: Kristofer Andreasson
investigator title: MD, PhD
mesh term: Arthritis
mesh term: Arthritis, Rheumatoid
sharing ipd: No