<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/NCT03808506</url>
  </required_header>
  <id_info>
    <org_study_id>113446</org_study_id>
    <nct_id>NCT03808506</nct_id>
  </id_info>
  <brief_title>Relationship Between Baseline Burden of Disease and TDM in Ulcerative Colitis</brief_title>
  <official_title>Relationship Between Baseline Burden of Disease and Anti-TNF Drug Trough Levels in Ulcerative Colitis.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lawson Health Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Lawson Health Research Institute</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>
      Ulcerative colitis (UC) is a chronic inflammatory bowel disease which often follows a&#xD;
      relapsing/remitting course. Anti-TNF therapies are proven to be effective in UC and studies&#xD;
      indicate that having adequate drug levels correlate with improved patient outcomes. It is&#xD;
      unknown, however, if a high burden of disease at baseline impacts drug utilization or loss.&#xD;
      In this study, we investigate whether measures of high burden of disease (fecal calprotectin,&#xD;
      bowel ultrasound, and colonoscopy) at baseline predicts low drug levels after standard&#xD;
      anti-TNF induction therapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Biologic therapy has revolutionized the treatment of IBD. Over the past 20 years, a&#xD;
      significant amount of research has been done to optimize biologic therapy using therapeutic&#xD;
      drug monitoring (TDM). Evidence is accumulating suggesting that insufficient anti-TNF drug&#xD;
      levels +/- development of anti-drug antibodies result in lower clinical efficacy, reduced&#xD;
      mucosal healing, and loss of response. The pharmacokinetics of anti-TNF drug clearance&#xD;
      leading to sub-therapeutic or absent drug levels can vary between and within any given&#xD;
      patient. Clearance may be dependent on many factors such as severity of inflammation, total&#xD;
      burden of disease, body weight, serum albumin levels, loss of drug through leaking into the&#xD;
      stool, and immune mediated pathways with the development of anti-drug antibodies. Standard&#xD;
      induction dosing does not take into account the severity and total burden of disease, which&#xD;
      may have significant effects on the elimination of circulating drug.&#xD;
&#xD;
      Most data surrounding TDM pertain to maintenance of remission, during a relatively stable&#xD;
      state of low burden of disease. Much less is known surrounding active drug levels during or&#xD;
      immediately after induction therapy, at which point disease burden is relatively high and&#xD;
      fluctuating. Some studies suggest improved response rates in those with higher anti-TNF drug&#xD;
      levels during this phase of therapy. A retrospective study by Gibson et al assessed&#xD;
      inpatients with acute severe ulcerative colitis and demonstrated reduction in colectomy rates&#xD;
      in those who received accelerated and intensified infliximab induction therapy. Although&#xD;
      trough levels were not provided in this study, the results suggest that standard induction&#xD;
      dosing may be suboptimal in a setting of high burden of disease.&#xD;
&#xD;
      Colonoscopy is considered the gold standard in regards to determining burden of active&#xD;
      disease in ulcerative colitis. However, it is invasive, requires endoscopy time, and carries&#xD;
      risk. Non-invasive methods to determine the presence and extent of inflammation is of&#xD;
      clinical and research interest. Fecal calprotectin (FC) is a promising tool which has now&#xD;
      been incorporated into standard clinical care of IBD patients. It is used to monitor disease&#xD;
      activity, assess response to therapy, and prognosticate future clinical relapse. Several&#xD;
      meta-analyses demonstrate the correlation between FC with endoscopic disease scores in both&#xD;
      Crohn's disease (CD) and Ulcerative Colitis (UC) with a pooled sensitivity of 85-92% and&#xD;
      specificity of 75-88%.&#xD;
&#xD;
      Bowel Ultrasound (US) is another non-invasive method to assess inflammatory activity in UC,&#xD;
      and is used in routine clinical practice. Bowel US correlates to inflammatory activity on&#xD;
      colonoscopy and can be used to assess response to therapy and prognosticate future relapse. A&#xD;
      benefit of sonography, as compared to colonoscopy and FC, is its ability to identify&#xD;
      inflammatory changes deep to the superficial mucosa. This may provide additional information&#xD;
      for burden of disease not recognized by other modalities. It is currently unknown if the&#xD;
      burden of disease as found on sonography influences drug elimination and the resultant trough&#xD;
      levels after induction therapy.&#xD;
&#xD;
      It is unknown if a high burden of disease at baseline impacts drug utilization or loss. In&#xD;
      this study, measures of burden of disease (FC, bowel US, and colonoscopy) at baseline will be&#xD;
      correlated to drug levels after standard anti-TNF induction therapy. It is hypothesized that&#xD;
      a high burden of disease leads to low drug levels after standard induction dosing.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    no recruitment during COVID pandemic&#xD;
  </why_stopped>
  <start_date type="Actual">September 1, 2019</start_date>
  <completion_date type="Actual">July 19, 2022</completion_date>
  <primary_completion_date type="Actual">June 19, 2022</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>Baseline fecal calprotectin concentration</measure>
    <time_frame>Performed within 4 weeks of starting adalimumab therapy</time_frame>
    <description>Fecal calprotectin concentration at baseline prior to starting adalimumab therapy. Fecal Calprotectin will be used as the primary outcome measure to determine burden of inflammation</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Post Induction fecal calprotectin concentration</measure>
    <time_frame>Performed 6 weeks post induction therapy</time_frame>
    <description>Fecal calprotectin concentration will be re-assessed at week 6 after starting adalimumab therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Baseline Mayo Endoscopic Score</measure>
    <time_frame>Performed within 12 weeks of study entry</time_frame>
    <description>Baseline endoscopic score (as assessed by colonoscopy or flexible sigmoidoscopy) to grade the severity of mucosal inflammation. The Mayo Endoscopic score is a standard, validated, and accepted grading systems which grades inflammation from 0-3.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Baseline bowel ultrasound inflammatory score</measure>
    <time_frame>Performed within 12 weeks of starting adalimumab therapy</time_frame>
    <description>Baseline severity of inflammation based on sonographic features including bowel wall thickness, depth of mural inflammation, and degree of hypervascularity. Each component will be scored from 0-3 resulting in an ultrasound severity score of 0-9 for the segment assessed. Three segments of the colon (right colon, transverse, left colon) will be assessed and scores combined to give a total inflammatory score.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">0</enrollment>
  <condition>Ulcerative Colitis</condition>
  <arm_group>
    <arm_group_label>Ulcerative colitis patients</arm_group_label>
    <description>Patients with documented ulcerative colitis who are initiating adalimumab therapy will have baseline bowel ultrasound and fecal calprotectin completed.</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Fecal calprotectin</intervention_name>
    <description>Stool test to look at baseline burden of inflammation</description>
    <arm_group_label>Ulcerative colitis patients</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Adult patients with documented ulcerative colitis with active inflammation who are starting&#xD;
        adalimumab therapy. All other concomittant therapies are allowed.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult outpatients &gt;=18 y of age with a confirmed diagnosis of ulcerative colitis&#xD;
&#xD;
          2. Patients beginning adalimumab for active disease as clinically indicated according to&#xD;
             the treating physician's discretion, either biologic naïve or switching biologic due&#xD;
             to failure of prior biologic therapy&#xD;
&#xD;
          3. Have had a colonoscopy or flexible sigmoidoscopy within 12 weeks of study entry&#xD;
&#xD;
          4. Any other concomitant therapies are allowed (including 5'ASA, corticosteroids,&#xD;
             azathioprine, and methotrexate).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Inability to provide informed consent&#xD;
&#xD;
          2. Inability to provide a fecal calprotectin&#xD;
&#xD;
          3. Contraindication to starting anti-TNF 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>Brian Yan, H.B Sc, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Western University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>London Health Sciences Center</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6A5W9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <reference>
    <citation>Vande Casteele N, Herfarth H, Katz J, Falck-Ytter Y, Singh S. American Gastroenterological Association Institute Technical Review on the Role of Therapeutic Drug Monitoring in the Management of Inflammatory Bowel Diseases. Gastroenterology. 2017 Sep;153(3):835-857.e6. doi: 10.1053/j.gastro.2017.07.031. Epub 2017 Jul 31.</citation>
    <PMID>28774547</PMID>
  </reference>
  <reference>
    <citation>Mitrev N, Vande Casteele N, Seow CH, Andrews JM, Connor SJ, Moore GT, Barclay M, Begun J, Bryant R, Chan W, Corte C, Ghaly S, Lemberg DA, Kariyawasam V, Lewindon P, Martin J, Mountifield R, Radford-Smith G, Slobodian P, Sparrow M, Toong C, van Langenberg D, Ward MG, Leong RW; IBD Sydney Organisation and the Australian Inflammatory Bowel Diseases Consensus Working Group. Review article: consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases. Aliment Pharmacol Ther. 2017 Dec;46(11-12):1037-1053. doi: 10.1111/apt.14368. Epub 2017 Oct 13.</citation>
    <PMID>29027257</PMID>
  </reference>
  <reference>
    <citation>Steenholdt C, Bendtzen K, Brynskov J, Ainsworth MA. Optimizing Treatment with TNF Inhibitors in Inflammatory Bowel Disease by Monitoring Drug Levels and Antidrug Antibodies. Inflamm Bowel Dis. 2016 Aug;22(8):1999-2015. doi: 10.1097/MIB.0000000000000772.</citation>
    <PMID>27135483</PMID>
  </reference>
  <reference>
    <citation>Maser EA, Villela R, Silverberg MS, Greenberg GR. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn's disease. Clin Gastroenterol Hepatol. 2006 Oct;4(10):1248-54. doi: 10.1016/j.cgh.2006.06.025. Epub 2006 Aug 22.</citation>
    <PMID>16931170</PMID>
  </reference>
  <reference>
    <citation>Paul S, Del Tedesco E, Marotte H, Rinaudo-Gaujous M, Moreau A, Phelip JM, Genin C, Peyrin-Biroulet L, Roblin X. Therapeutic drug monitoring of infliximab and mucosal healing in inflammatory bowel disease: a prospective study. Inflamm Bowel Dis. 2013 Nov;19(12):2568-76. doi: 10.1097/MIB.0b013e3182a77b41.</citation>
    <PMID>24013361</PMID>
  </reference>
  <reference>
    <citation>Ricciuto A, Dhaliwal J, Walters TD, Griffiths AM, Church PC. Clinical Outcomes With Therapeutic Drug Monitoring in Inflammatory Bowel Disease: A Systematic Review With Meta-Analysis. J Crohns Colitis. 2018 Nov 15;12(11):1302-1315. doi: 10.1093/ecco-jcc/jjy109.</citation>
    <PMID>30107416</PMID>
  </reference>
  <reference>
    <citation>Berends SE, Strik AS, Lowenberg M, D'Haens GR, Mathot RAA. Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis. Clin Pharmacokinet. 2019 Jan;58(1):15-37. doi: 10.1007/s40262-018-0676-z.</citation>
    <PMID>29752633</PMID>
  </reference>
  <reference>
    <citation>Berends SE, Strik AS, Van Selm JC, Lowenberg M, Ponsioen CY, D'Haens GR, Mathot RA. Explaining Interpatient Variability in Adalimumab Pharmacokinetics in Patients With Crohn's Disease. Ther Drug Monit. 2018 Apr;40(2):202-211. doi: 10.1097/FTD.0000000000000494.</citation>
    <PMID>29529008</PMID>
  </reference>
  <reference>
    <citation>Brandse JF, van den Brink GR, Wildenberg ME, van der Kleij D, Rispens T, Jansen JM, Mathot RA, Ponsioen CY, Lowenberg M, D'Haens GR. Loss of Infliximab Into Feces Is Associated With Lack of Response to Therapy in Patients With Severe Ulcerative Colitis. Gastroenterology. 2015 Aug;149(2):350-5.e2. doi: 10.1053/j.gastro.2015.04.016. Epub 2015 Apr 25.</citation>
    <PMID>25917786</PMID>
  </reference>
  <reference>
    <citation>Brandse JF, Mathot RA, van der Kleij D, Rispens T, Ashruf Y, Jansen JM, Rietdijk S, Lowenberg M, Ponsioen CY, Singh S, van den Brink GR, D'Haens GR. Pharmacokinetic Features and Presence of Antidrug Antibodies Associate With Response to Infliximab Induction Therapy in Patients With Moderate to Severe Ulcerative Colitis. Clin Gastroenterol Hepatol. 2016 Feb;14(2):251-8.e1-2. doi: 10.1016/j.cgh.2015.10.029. Epub 2015 Nov 9.</citation>
    <PMID>26545802</PMID>
  </reference>
  <reference>
    <citation>Brandse JF, Mould D, Smeekes O, Ashruf Y, Kuin S, Strik A, van den Brink GR, D'Haens GR. A Real-life Population Pharmacokinetic Study Reveals Factors Associated with Clearance and Immunogenicity of Infliximab in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2017 Apr;23(4):650-660. doi: 10.1097/MIB.0000000000001043.</citation>
    <PMID>28195852</PMID>
  </reference>
  <reference>
    <citation>Papamichael K, Cheifetz AS. Therapeutic Drug Monitoring in IBD: The New Standard-of-Care for Anti-TNF Therapy. Am J Gastroenterol. 2017 May;112(5):673-676. doi: 10.1038/ajg.2017.21. Epub 2017 Feb 21. No abstract available.</citation>
    <PMID>28220781</PMID>
  </reference>
  <reference>
    <citation>Papamichael K, Vande Casteele N, Ferrante M, Gils A, Cheifetz AS. Therapeutic Drug Monitoring During Induction of Anti-Tumor Necrosis Factor Therapy in Inflammatory Bowel Disease: Defining a Therapeutic Drug Window. Inflamm Bowel Dis. 2017 Sep;23(9):1510-1515. doi: 10.1097/MIB.0000000000001231.</citation>
    <PMID>28816757</PMID>
  </reference>
  <reference>
    <citation>Papamichael K, Baert F, Tops S, Assche GV, Rutgeerts P, Vermeire S, Gils A, Ferrante M. Post-Induction Adalimumab Concentration is Associated with Short-Term Mucosal Healing in Patients with Ulcerative Colitis. J Crohns Colitis. 2017 Jan;11(1):53-59. doi: 10.1093/ecco-jcc/jjw122. Epub 2016 Jul 11.</citation>
    <PMID>27402915</PMID>
  </reference>
  <reference>
    <citation>Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010 Jan;59(1):49-54. doi: 10.1136/gut.2009.183095.</citation>
    <PMID>19651627</PMID>
  </reference>
  <reference>
    <citation>Gibson DJ, Heetun ZS, Redmond CE, Nanda KS, Keegan D, Byrne K, Mulcahy HE, Cullen G, Doherty GA. An accelerated infliximab induction regimen reduces the need for early colectomy in patients with acute severe ulcerative colitis. Clin Gastroenterol Hepatol. 2015 Feb;13(2):330-335.e1. doi: 10.1016/j.cgh.2014.07.041. Epub 2014 Jul 30.</citation>
    <PMID>25086187</PMID>
  </reference>
  <reference>
    <citation>Mumolo MG, Bertani L, Ceccarelli L, Laino G, Di Fluri G, Albano E, Tapete G, Costa F. From bench to bedside: Fecal calprotectin in inflammatory bowel diseases clinical setting. World J Gastroenterol. 2018 Sep 7;24(33):3681-3694. doi: 10.3748/wjg.v24.i33.3681.</citation>
    <PMID>30197475</PMID>
  </reference>
  <reference>
    <citation>Rokkas T, Portincasa P, Koutroubakis IE. Fecal calprotectin in assessing inflammatory bowel disease endoscopic activity: a diagnostic accuracy meta-analysis. J Gastrointestin Liver Dis. 2018 Sep;27(3):299-306. doi: 10.15403/jgld.2014.1121.273.pti.</citation>
    <PMID>30240474</PMID>
  </reference>
  <reference>
    <citation>Mosli MH, Zou G, Garg SK, Feagan SG, MacDonald JK, Chande N, Sandborn WJ, Feagan BG. C-Reactive Protein, Fecal Calprotectin, and Stool Lactoferrin for Detection of Endoscopic Activity in Symptomatic Inflammatory Bowel Disease Patients: A Systematic Review and Meta-Analysis. Am J Gastroenterol. 2015 Jun;110(6):802-19; quiz 820. doi: 10.1038/ajg.2015.120. Epub 2015 May 12.</citation>
    <PMID>25964225</PMID>
  </reference>
  <reference>
    <citation>Parente F, Molteni M, Marino B, Colli A, Ardizzone S, Greco S, Sampietro G, Foschi D, Gallus S. Are colonoscopy and bowel ultrasound useful for assessing response to short-term therapy and predicting disease outcome of moderate-to-severe forms of ulcerative colitis?: a prospective study. Am J Gastroenterol. 2010 May;105(5):1150-7. doi: 10.1038/ajg.2009.672. Epub 2009 Dec 8.</citation>
    <PMID>19997096</PMID>
  </reference>
  <reference>
    <citation>Horsthuis K, Bipat S, Bennink RJ, Stoker J. Inflammatory bowel disease diagnosed with US, MR, scintigraphy, and CT: meta-analysis of prospective studies. Radiology. 2008 Apr;247(1):64-79. doi: 10.1148/radiol.2471070611.</citation>
    <PMID>18372465</PMID>
  </reference>
  <reference>
    <citation>Sey MS, Gregor J, Chande N, Ponich T, Bhaduri M, Lum A, Zaleski W, Yan B. Transcutaneous bowel sonography for inflammatory bowel disease is sensitive and specific when performed in a nonexpert low-volume North American center. J Ultrasound Med. 2013 Aug;32(8):1413-7. doi: 10.7863/ultra.32.8.1413.</citation>
    <PMID>23887951</PMID>
  </reference>
  <reference>
    <citation>Yan B, Feagan B, Teriaky A, Mosli M, Mohamed R, Williams G, Yeung E, Yong E, Haig A, Sey M, Stitt L, Zou GY, Jairath V. Reliability of EUS indices to detect inflammation in ulcerative colitis. Gastrointest Endosc. 2017 Dec;86(6):1079-1087. doi: 10.1016/j.gie.2017.07.035. Epub 2017 Jul 29.</citation>
    <PMID>28760533</PMID>
  </reference>
  <reference>
    <citation>Lachin JM. Introduction to sample size determination and power analysis for clinical trials. Control Clin Trials. 1981 Jun;2(2):93-113. doi: 10.1016/0197-2456(81)90001-5.</citation>
    <PMID>7273794</PMID>
  </reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>January 14, 2019</study_first_submitted>
  <study_first_submitted_qc>January 15, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 17, 2019</study_first_posted>
  <last_update_submitted>March 7, 2023</last_update_submitted>
  <last_update_submitted_qc>March 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 9, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Lawson Health Research Institute</investigator_affiliation>
    <investigator_full_name>Brian Yan</investigator_full_name>
    <investigator_title>Associate Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>Ulcerative colitis</keyword>
  <keyword>Therapeutic drug monitoring</keyword>
  <keyword>fecal calprotectin</keyword>
  <keyword>adalimumab</keyword>
  <keyword>bowel ultrasound</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colitis</mesh_term>
    <mesh_term>Colitis, Ulcerative</mesh_term>
    <mesh_term>Ulcer</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/NCT03808506
org study id: 113446
nct id: NCT03808506
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Ulcerative colitis (UC) is a chronic inflammatory bowel disease which often follows a
      relapsing/remitting course. Anti-TNF therapies are proven to be effective in UC and studies
      indicate that having adequate drug levels correlate with improved patient outcomes. It is
      unknown, however, if a high burden of disease at baseline impacts drug utilization or loss.
      In this study, we investigate whether measures of high burden of disease (fecal calprotectin,
      bowel ultrasound, and colonoscopy) at baseline predicts low drug levels after standard
      anti-TNF induction therapy.
Biologic therapy has revolutionized the treatment of IBD. Over the past 20 years, a
      significant amount of research has been done to optimize biologic therapy using therapeutic
      drug monitoring (TDM). Evidence is accumulating suggesting that insufficient anti-TNF drug
      levels +/- development of anti-drug antibodies result in lower clinical efficacy, reduced
      mucosal healing, and loss of response. The pharmacokinetics of anti-TNF drug clearance
      leading to sub-therapeutic or absent drug levels can vary between and within any given
      patient. Clearance may be dependent on many factors such as severity of inflammation, total
      burden of disease, body weight, serum albumin levels, loss of drug through leaking into the
      stool, and immune mediated pathways with the development of anti-drug antibodies. Standard
      induction dosing does not take into account the severity and total burden of disease, which
      may have significant effects on the elimination of circulating drug.

      Most data surrounding TDM pertain to maintenance of remission, during a relatively stable
      state of low burden of disease. Much less is known surrounding active drug levels during or
      immediately after induction therapy, at which point disease burden is relatively high and
      fluctuating. Some studies suggest improved response rates in those with higher anti-TNF drug
      levels during this phase of therapy. A retrospective study by Gibson et al assessed
      inpatients with acute severe ulcerative colitis and demonstrated reduction in colectomy rates
      in those who received accelerated and intensified infliximab induction therapy. Although
      trough levels were not provided in this study, the results suggest that standard induction
      dosing may be suboptimal in a setting of high burden of disease.

      Colonoscopy is considered the gold standard in regards to determining burden of active
      disease in ulcerative colitis. However, it is invasive, requires endoscopy time, and carries
      risk. Non-invasive methods to determine the presence and extent of inflammation is of
      clinical and research interest. Fecal calprotectin (FC) is a promising tool which has now
      been incorporated into standard clinical care of IBD patients. It is used to monitor disease
      activity, assess response to therapy, and prognosticate future clinical relapse. Several
      meta-analyses demonstrate the correlation between FC with endoscopic disease scores in both
      Crohn's disease (CD) and Ulcerative Colitis (UC) with a pooled sensitivity of 85-92% and
      specificity of 75-88%.

      Bowel Ultrasound (US) is another non-invasive method to assess inflammatory activity in UC,
      and is used in routine clinical practice. Bowel US correlates to inflammatory activity on
      colonoscopy and can be used to assess response to therapy and prognosticate future relapse. A
      benefit of sonography, as compared to colonoscopy and FC, is its ability to identify
      inflammatory changes deep to the superficial mucosa. This may provide additional information
      for burden of disease not recognized by other modalities. It is currently unknown if the
      burden of disease as found on sonography influences drug elimination and the resultant trough
      levels after induction therapy.

      It is unknown if a high burden of disease at baseline impacts drug utilization or loss. In
      this study, measures of burden of disease (FC, bowel US, and colonoscopy) at baseline will be
      correlated to drug levels after standard anti-TNF induction therapy. It is hypothesized that
      a high burden of disease leads to low drug levels after standard induction dosing.
observational model: Cohort
time perspective: Prospective
measure: Baseline fecal calprotectin concentration
time frame: Performed within 4 weeks of starting adalimumab therapy
description: Fecal calprotectin concentration at baseline prior to starting adalimumab therapy. Fecal Calprotectin will be used as the primary outcome measure to determine burden of inflammation
measure: Post Induction fecal calprotectin concentration
time frame: Performed 6 weeks post induction therapy
description: Fecal calprotectin concentration will be re-assessed at week 6 after starting adalimumab therapy
measure: Baseline Mayo Endoscopic Score
time frame: Performed within 12 weeks of study entry
description: Baseline endoscopic score (as assessed by colonoscopy or flexible sigmoidoscopy) to grade the severity of mucosal inflammation. The Mayo Endoscopic score is a standard, validated, and accepted grading systems which grades inflammation from 0-3.
measure: Baseline bowel ultrasound inflammatory score
time frame: Performed within 12 weeks of starting adalimumab therapy
description: Baseline severity of inflammation based on sonographic features including bowel wall thickness, depth of mural inflammation, and degree of hypervascularity. Each component will be scored from 0-3 resulting in an ultrasound severity score of 0-9 for the segment assessed. Three segments of the colon (right colon, transverse, left colon) will be assessed and scores combined to give a total inflammatory score.
arm group label: Ulcerative colitis patients
description: Patients with documented ulcerative colitis who are initiating adalimumab therapy will have baseline bowel ultrasound and fecal calprotectin completed.
intervention type: Diagnostic Test
intervention name: Fecal calprotectin
description: Stool test to look at baseline burden of inflammation
arm group label: Ulcerative colitis patients
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Brian Yan, H.B Sc, MD
role: Principal Investigator
affiliation: Western University
facility: 
country: Canada
citation: Vande Casteele N, Herfarth H, Katz J, Falck-Ytter Y, Singh S. American Gastroenterological Association Institute Technical Review on the Role of Therapeutic Drug Monitoring in the Management of Inflammatory Bowel Diseases. Gastroenterology. 2017 Sep;153(3):835-857.e6. doi: 10.1053/j.gastro.2017.07.031. Epub 2017 Jul 31.
PMID: 28774547
citation: Mitrev N, Vande Casteele N, Seow CH, Andrews JM, Connor SJ, Moore GT, Barclay M, Begun J, Bryant R, Chan W, Corte C, Ghaly S, Lemberg DA, Kariyawasam V, Lewindon P, Martin J, Mountifield R, Radford-Smith G, Slobodian P, Sparrow M, Toong C, van Langenberg D, Ward MG, Leong RW; IBD Sydney Organisation and the Australian Inflammatory Bowel Diseases Consensus Working Group. Review article: consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases. Aliment Pharmacol Ther. 2017 Dec;46(11-12):1037-1053. doi: 10.1111/apt.14368. Epub 2017 Oct 13.
PMID: 29027257
citation: Steenholdt C, Bendtzen K, Brynskov J, Ainsworth MA. Optimizing Treatment with TNF Inhibitors in Inflammatory Bowel Disease by Monitoring Drug Levels and Antidrug Antibodies. Inflamm Bowel Dis. 2016 Aug;22(8):1999-2015. doi: 10.1097/MIB.0000000000000772.
PMID: 27135483
citation: Maser EA, Villela R, Silverberg MS, Greenberg GR. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn's disease. Clin Gastroenterol Hepatol. 2006 Oct;4(10):1248-54. doi: 10.1016/j.cgh.2006.06.025. Epub 2006 Aug 22.
PMID: 16931170
citation: Paul S, Del Tedesco E, Marotte H, Rinaudo-Gaujous M, Moreau A, Phelip JM, Genin C, Peyrin-Biroulet L, Roblin X. Therapeutic drug monitoring of infliximab and mucosal healing in inflammatory bowel disease: a prospective study. Inflamm Bowel Dis. 2013 Nov;19(12):2568-76. doi: 10.1097/MIB.0b013e3182a77b41.
PMID: 24013361
citation: Ricciuto A, Dhaliwal J, Walters TD, Griffiths AM, Church PC. Clinical Outcomes With Therapeutic Drug Monitoring in Inflammatory Bowel Disease: A Systematic Review With Meta-Analysis. J Crohns Colitis. 2018 Nov 15;12(11):1302-1315. doi: 10.1093/ecco-jcc/jjy109.
PMID: 30107416
citation: Berends SE, Strik AS, Lowenberg M, D'Haens GR, Mathot RAA. Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis. Clin Pharmacokinet. 2019 Jan;58(1):15-37. doi: 10.1007/s40262-018-0676-z.
PMID: 29752633
citation: Berends SE, Strik AS, Van Selm JC, Lowenberg M, Ponsioen CY, D'Haens GR, Mathot RA. Explaining Interpatient Variability in Adalimumab Pharmacokinetics in Patients With Crohn's Disease. Ther Drug Monit. 2018 Apr;40(2):202-211. doi: 10.1097/FTD.0000000000000494.
PMID: 29529008
citation: Brandse JF, van den Brink GR, Wildenberg ME, van der Kleij D, Rispens T, Jansen JM, Mathot RA, Ponsioen CY, Lowenberg M, D'Haens GR. Loss of Infliximab Into Feces Is Associated With Lack of Response to Therapy in Patients With Severe Ulcerative Colitis. Gastroenterology. 2015 Aug;149(2):350-5.e2. doi: 10.1053/j.gastro.2015.04.016. Epub 2015 Apr 25.
PMID: 25917786
citation: Brandse JF, Mathot RA, van der Kleij D, Rispens T, Ashruf Y, Jansen JM, Rietdijk S, Lowenberg M, Ponsioen CY, Singh S, van den Brink GR, D'Haens GR. Pharmacokinetic Features and Presence of Antidrug Antibodies Associate With Response to Infliximab Induction Therapy in Patients With Moderate to Severe Ulcerative Colitis. Clin Gastroenterol Hepatol. 2016 Feb;14(2):251-8.e1-2. doi: 10.1016/j.cgh.2015.10.029. Epub 2015 Nov 9.
PMID: 26545802
citation: Brandse JF, Mould D, Smeekes O, Ashruf Y, Kuin S, Strik A, van den Brink GR, D'Haens GR. A Real-life Population Pharmacokinetic Study Reveals Factors Associated with Clearance and Immunogenicity of Infliximab in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2017 Apr;23(4):650-660. doi: 10.1097/MIB.0000000000001043.
PMID: 28195852
citation: Papamichael K, Cheifetz AS. Therapeutic Drug Monitoring in IBD: The New Standard-of-Care for Anti-TNF Therapy. Am J Gastroenterol. 2017 May;112(5):673-676. doi: 10.1038/ajg.2017.21. Epub 2017 Feb 21. No abstract available.
PMID: 28220781
citation: Papamichael K, Vande Casteele N, Ferrante M, Gils A, Cheifetz AS. Therapeutic Drug Monitoring During Induction of Anti-Tumor Necrosis Factor Therapy in Inflammatory Bowel Disease: Defining a Therapeutic Drug Window. Inflamm Bowel Dis. 2017 Sep;23(9):1510-1515. doi: 10.1097/MIB.0000000000001231.
PMID: 28816757
citation: Papamichael K, Baert F, Tops S, Assche GV, Rutgeerts P, Vermeire S, Gils A, Ferrante M. Post-Induction Adalimumab Concentration is Associated with Short-Term Mucosal Healing in Patients with Ulcerative Colitis. J Crohns Colitis. 2017 Jan;11(1):53-59. doi: 10.1093/ecco-jcc/jjw122. Epub 2016 Jul 11.
PMID: 27402915
citation: Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010 Jan;59(1):49-54. doi: 10.1136/gut.2009.183095.
PMID: 19651627
citation: Gibson DJ, Heetun ZS, Redmond CE, Nanda KS, Keegan D, Byrne K, Mulcahy HE, Cullen G, Doherty GA. An accelerated infliximab induction regimen reduces the need for early colectomy in patients with acute severe ulcerative colitis. Clin Gastroenterol Hepatol. 2015 Feb;13(2):330-335.e1. doi: 10.1016/j.cgh.2014.07.041. Epub 2014 Jul 30.
PMID: 25086187
citation: Mumolo MG, Bertani L, Ceccarelli L, Laino G, Di Fluri G, Albano E, Tapete G, Costa F. From bench to bedside: Fecal calprotectin in inflammatory bowel diseases clinical setting. World J Gastroenterol. 2018 Sep 7;24(33):3681-3694. doi: 10.3748/wjg.v24.i33.3681.
PMID: 30197475
citation: Rokkas T, Portincasa P, Koutroubakis IE. Fecal calprotectin in assessing inflammatory bowel disease endoscopic activity: a diagnostic accuracy meta-analysis. J Gastrointestin Liver Dis. 2018 Sep;27(3):299-306. doi: 10.15403/jgld.2014.1121.273.pti.
PMID: 30240474
citation: Mosli MH, Zou G, Garg SK, Feagan SG, MacDonald JK, Chande N, Sandborn WJ, Feagan BG. C-Reactive Protein, Fecal Calprotectin, and Stool Lactoferrin for Detection of Endoscopic Activity in Symptomatic Inflammatory Bowel Disease Patients: A Systematic Review and Meta-Analysis. Am J Gastroenterol. 2015 Jun;110(6):802-19; quiz 820. doi: 10.1038/ajg.2015.120. Epub 2015 May 12.
PMID: 25964225
citation: Parente F, Molteni M, Marino B, Colli A, Ardizzone S, Greco S, Sampietro G, Foschi D, Gallus S. Are colonoscopy and bowel ultrasound useful for assessing response to short-term therapy and predicting disease outcome of moderate-to-severe forms of ulcerative colitis?: a prospective study. Am J Gastroenterol. 2010 May;105(5):1150-7. doi: 10.1038/ajg.2009.672. Epub 2009 Dec 8.
PMID: 19997096
citation: Horsthuis K, Bipat S, Bennink RJ, Stoker J. Inflammatory bowel disease diagnosed with US, MR, scintigraphy, and CT: meta-analysis of prospective studies. Radiology. 2008 Apr;247(1):64-79. doi: 10.1148/radiol.2471070611.
PMID: 18372465
citation: Sey MS, Gregor J, Chande N, Ponich T, Bhaduri M, Lum A, Zaleski W, Yan B. Transcutaneous bowel sonography for inflammatory bowel disease is sensitive and specific when performed in a nonexpert low-volume North American center. J Ultrasound Med. 2013 Aug;32(8):1413-7. doi: 10.7863/ultra.32.8.1413.
PMID: 23887951
citation: Yan B, Feagan B, Teriaky A, Mosli M, Mohamed R, Williams G, Yeung E, Yong E, Haig A, Sey M, Stitt L, Zou GY, Jairath V. Reliability of EUS indices to detect inflammation in ulcerative colitis. Gastrointest Endosc. 2017 Dec;86(6):1079-1087. doi: 10.1016/j.gie.2017.07.035. Epub 2017 Jul 29.
PMID: 28760533
citation: Lachin JM. Introduction to sample size determination and power analysis for clinical trials. Control Clin Trials. 1981 Jun;2(2):93-113. doi: 10.1016/0197-2456(81)90001-5.
PMID: 7273794
responsible party type: Principal Investigator
investigator affiliation: Lawson Health Research Institute
investigator full name: Brian Yan
investigator title: Associate Professor of Medicine
mesh term: Colitis
mesh term: Colitis, Ulcerative
mesh term: Ulcer
sharing ipd: No