<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/NCT04425993</url>
  </required_header>
  <id_info>
    <org_study_id>KY20200522-4</org_study_id>
    <nct_id>NCT04425993</nct_id>
  </id_info>
  <brief_title>Rectal Indomethacin Versus Rectal Indomethacin and Sublingual Nitrate for PEP Prevention</brief_title>
  <official_title>Rectal Indomethacin Versus Rectal Indomethacin and Sublingual Nitrate to Prevent Post-ERCP Pancreatitis: a Multicentre, Non-inferiority, Double-blind, Randomised Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Air Force Military Medical University, China</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Air Force Military Medical University, China</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) are at risk for&#xD;
      post-ERCP pancreatitis (PEP), which is associated with adverse outcomes. Combination&#xD;
      prophylaxis strategies are increasingly investigated to prevent PEP more effectively, and&#xD;
      studies have confirmed the benefits. Two randomized controlled trials revealed that&#xD;
      combination prophylaxis with rectal NSAIDs and sublingual nitrate has reduced PEP rates to&#xD;
      5.6%-6.7% in average-risk patients. However, there was concern regarding the safety of&#xD;
      sublingual nitrate with reports of significant increasing the risk of hypotesion (rate of&#xD;
      54.9%) and headache (rate of 4.1%) as compared with placebo.&#xD;
&#xD;
      As a safety drug, rectal administration of one dose NSAIDs is recommended as basic&#xD;
      chemoprophylaxis in common or high-risk patients in guidelines. Results from previous studies&#xD;
      showed rectal administration of NSAIDs significantly reduced PEP rate to 4-5.3% in&#xD;
      average-risk patients. Although the difference in demographics, study design and outcomes&#xD;
      definition, evidence was obtained that rectal NSAIDS was associated with similar PEP rate as&#xD;
      combination prophylaxis with rectal NSAIDs and sublingual nitrate. However, evidence is&#xD;
      lacking from large, randomized clinical trials indicating that efficiency of PEP prevention&#xD;
      with rectal NSAIDs alone is not inferior to with combination prophylaxis. The investigators&#xD;
      conduct this trial to investigate the hypothesis that rectal NSAIDs alone is non-inferior to&#xD;
      the combination prophylaxis in terms of PEP prevention, but with reduce side effect.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">July 1, 2020</start_date>
  <completion_date type="Anticipated">December 30, 2022</completion_date>
  <primary_completion_date type="Anticipated">May 30, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of post-ERCP Pancreatitis</measure>
    <time_frame>14 days</time_frame>
    <description>The diagnosis of PEP was established if there was new onset of upper abdominal pain associated with an increased amylase or lipase level of at least 3 times the upper limit of normal range at 24 hours after the procedure, and hospitalization for at least 2 nights. Doctors are advised to use cross-sectional imaging to identify ambiguous PEP.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rate of moderate to severe PEP</measure>
    <time_frame>14 days</time_frame>
    <description>The severity classification of pancreatitis was defined according to the criteria of Cotton et al and the revised Atlanta criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Other adverse events</measure>
    <time_frame>14 days</time_frame>
    <description>Adverse effects of indomethacin, including gastrointestinal bleeding and renal failure.&#xD;
Adverse effects of nitrates, including hypotension, headache and dizziness. Other post-ERCP adverse events including cholangitis, bleeding, and perforation.&#xD;
Any other adverse outcomes possibly related to ERCP or experimental drugs that required hospital admission or a prolonged hospital stay for further management.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">2700</enrollment>
  <condition>Post-ERCP Acute Pancreatitis</condition>
  <arm_group>
    <arm_group_label>Rectal indomethacin and sublingual nitrate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All patients without contraindications should receive sublingual isosorbide dinitrate within 5 min before ERCP.&#xD;
All patients without contraindications should receive rectal indomethacin within 30 min before ERCP.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Rectal indomethacin and sublingual placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>All patients without contraindications should receive sublingual placebo within 5 min before ERCP.&#xD;
All patients without contraindications should receive rectal indomethacin within 30 min before ERCP.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Rectal placebo and sublingual nitrate</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>All patients without contraindications should receive sublingual isosorbide dinitrate within 5 min before ERCP.&#xD;
All patients without contraindications should receive rectal placebo within 30 min before ERCP.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Rectal placebo and sublingual placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>All patients without contraindications should receive sublingual placebo within 5 min before ERCP.&#xD;
All patients without contraindications should receive rectal placebo within 30 min before ERCP.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Isosorbide Dinitrate 5 MG</intervention_name>
    <description>All patients without contraindications should receive sublingual isosorbide dinitrate tablet within 5 minutes before ERCP.</description>
    <arm_group_label>Rectal indomethacin and sublingual nitrate</arm_group_label>
    <arm_group_label>Rectal placebo and sublingual nitrate</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Indomethacin 100 MG</intervention_name>
    <description>All patients without contraindications should receive rectal indomethacin within 30 min before ERCP.</description>
    <arm_group_label>Rectal indomethacin and sublingual nitrate</arm_group_label>
    <arm_group_label>Rectal indomethacin and sublingual placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sublingual Placebo</intervention_name>
    <description>All patients without contraindications should receive sublingual placebo within 5 minutes before ERCP.</description>
    <arm_group_label>Rectal indomethacin and sublingual placebo</arm_group_label>
    <arm_group_label>Rectal placebo and sublingual placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rectal placebo</intervention_name>
    <description>All patients without contraindications should receive rectal placebo within 30 min before ERCP.</description>
    <arm_group_label>Rectal placebo and sublingual nitrate</arm_group_label>
    <arm_group_label>Rectal placebo and sublingual placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients (age, 18-80 y) with native papilla planned for diagnostic or therapeutic ERCP&#xD;
             were eligible for enrollment in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  contraindications to ERCP;&#xD;
&#xD;
          -  allergy to nitrates or NSAIDs;&#xD;
&#xD;
          -  currently on nitrate medication;&#xD;
&#xD;
          -  receiving NSAIDs within 7 days;&#xD;
&#xD;
          -  not suitable for indomethacin eg, gastrointestinal hemorrhage within the past 4 weeks,&#xD;
             renal dysfunction (creatinine level &gt;1.4 mg/dL) or the presence of coagulopathy before&#xD;
             the procedure (international normalized ratio &gt; 1.5);&#xD;
&#xD;
          -  acute pancreatitis within 3 days;&#xD;
&#xD;
          -  pregnant or breastfeeding women;&#xD;
&#xD;
          -  unwilling or inability to provide consent.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Xiamen Humanity Hospital</name>
      <address>
        <city>Xiamen</city>
        <state>Fujian</state>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lanzhou University Second Hospital</name>
      <address>
        <city>Lanzhou</city>
        <state>Gansu</state>
        <zip>730030</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Xi'an Central Hospital</name>
      <address>
        <city>Xi'an</city>
        <state>Shaanxi</state>
        <zip>710032</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Xijing Hoapital</name>
      <address>
        <city>Xi'an</city>
        <state>Shaanxi</state>
        <zip>710032</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <citation>Sotoudehmanesh R, Eloubeidi MA, Asgari AA, Farsinejad M, Khatibian M. A randomized trial of rectal indomethacin and sublingual nitrates to prevent post-ERCP pancreatitis. Am J Gastroenterol. 2014 Jun;109(6):903-9. doi: 10.1038/ajg.2014.9. Epub 2014 Feb 11.</citation>
    <PMID>24513806</PMID>
  </reference>
  <reference>
    <citation>Tomoda T, Kato H, Ueki T, Akimoto Y, Hata H, Fujii M, Harada R, Ogawa T, Wato M, Takatani M, Matsubara M, Kawai Y, Okada H. Combination of Diclofenac and Sublingual Nitrates Is Superior to Diclofenac Alone in Preventing Pancreatitis After Endoscopic Retrograde Cholangiopancreatography. Gastroenterology. 2019 May;156(6):1753-1760.e1. doi: 10.1053/j.gastro.2019.01.267. Epub 2019 Feb 14.</citation>
    <PMID>30772342</PMID>
  </reference>
  <reference>
    <citation>Ding J, Jin X, Pan Y, Liu S, Li Y. Glyceryl trinitrate for prevention of post-ERCP pancreatitis and improve the rate of cannulation: a meta-analysis of prospective, randomized, controlled trials. PLoS One. 2013 Oct 1;8(10):e75645. doi: 10.1371/journal.pone.0075645. eCollection 2013.</citation>
    <PMID>24098392</PMID>
  </reference>
  <reference>
    <citation>Luo H, Zhao L, Leung J, Zhang R, Liu Z, Wang X, Wang B, Nie Z, Lei T, Li X, Zhou W, Zhang L, Wang Q, Li M, Zhou Y, Liu Q, Sun H, Wang Z, Liang S, Guo X, Tao Q, Wu K, Pan Y, Guo X, Fan D. Routine pre-procedural rectal indometacin versus selective post-procedural rectal indometacin to prevent pancreatitis in patients undergoing endoscopic retrograde cholangiopancreatography: a multicentre, single-blinded, randomised controlled trial. Lancet. 2016 Jun 4;387(10035):2293-2301. doi: 10.1016/S0140-6736(16)30310-5. Epub 2016 Apr 28.</citation>
    <PMID>27133971</PMID>
  </reference>
  <reference>
    <citation>Luo H, Wang X, Zhang R, Liang S, Kang X, Zhang X, Lou Q, Xiong K, Yang J, Si L, Liu W, Liu Y, Zhou Y, Wang S, Yang M, Chen W, Han Y, Shang G, Yang X, He Y, Zou Q, Guo W, Dai Y, Zeng W, Zhu X, Gong R, Li X, Nie Z, Wang Q, Wang L, Pan Y, Guo X, Fan D. Rectal Indomethacin and Spraying of Duodenal Papilla With Epinephrine Increases Risk of Pancreatitis Following Endoscopic Retrograde Cholangiopancreatography. Clin Gastroenterol Hepatol. 2019 Jul;17(8):1597-1606.e5. doi: 10.1016/j.cgh.2018.10.043. Epub 2018 Oct 31.</citation>
    <PMID>30391434</PMID>
  </reference>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>June 8, 2020</study_first_submitted>
  <study_first_submitted_qc>June 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>October 20, 2020</last_update_submitted>
  <last_update_submitted_qc>October 20, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 22, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Air Force Military Medical University, China</investigator_affiliation>
    <investigator_full_name>Yanglin Pan</investigator_full_name>
    <investigator_title>Associated professor</investigator_title>
  </responsible_party>
  <keyword>ERCP</keyword>
  <keyword>Post-ERCP pancreatitis</keyword>
  <keyword>PEP</keyword>
  <keyword>NSAIDs</keyword>
  <keyword>indomethacin</keyword>
  <keyword>nitrate</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pancreatitis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Indomethacin</mesh_term>
    <mesh_term>Isosorbide</mesh_term>
    <mesh_term>Isosorbide Dinitrate</mesh_term>
    <mesh_term>Isosorbide-5-mononitrate</mesh_term>
  </intervention_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/NCT04425993
org study id: KY20200522-4
nct id: NCT04425993
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) are at risk for
      post-ERCP pancreatitis (PEP), which is associated with adverse outcomes. Combination
      prophylaxis strategies are increasingly investigated to prevent PEP more effectively, and
      studies have confirmed the benefits. Two randomized controlled trials revealed that
      combination prophylaxis with rectal NSAIDs and sublingual nitrate has reduced PEP rates to
      5.6%-6.7% in average-risk patients. However, there was concern regarding the safety of
      sublingual nitrate with reports of significant increasing the risk of hypotesion (rate of
      54.9%) and headache (rate of 4.1%) as compared with placebo.

      As a safety drug, rectal administration of one dose NSAIDs is recommended as basic
      chemoprophylaxis in common or high-risk patients in guidelines. Results from previous studies
      showed rectal administration of NSAIDs significantly reduced PEP rate to 4-5.3% in
      average-risk patients. Although the difference in demographics, study design and outcomes
      definition, evidence was obtained that rectal NSAIDS was associated with similar PEP rate as
      combination prophylaxis with rectal NSAIDs and sublingual nitrate. However, evidence is
      lacking from large, randomized clinical trials indicating that efficiency of PEP prevention
      with rectal NSAIDs alone is not inferior to with combination prophylaxis. The investigators
      conduct this trial to investigate the hypothesis that rectal NSAIDs alone is non-inferior to
      the combination prophylaxis in terms of PEP prevention, but with reduce side effect.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Rate of post-ERCP Pancreatitis
time frame: 14 days
description: The diagnosis of PEP was established if there was new onset of upper abdominal pain associated with an increased amylase or lipase level of at least 3 times the upper limit of normal range at 24 hours after the procedure, and hospitalization for at least 2 nights. Doctors are advised to use cross-sectional imaging to identify ambiguous PEP.
measure: Rate of moderate to severe PEP
time frame: 14 days
description: The severity classification of pancreatitis was defined according to the criteria of Cotton et al and the revised Atlanta criteria.
measure: Other adverse events
time frame: 14 days
description: Adverse effects of indomethacin, including gastrointestinal bleeding and renal failure.
Adverse effects of nitrates, including hypotension, headache and dizziness. Other post-ERCP adverse events including cholangitis, bleeding, and perforation.
Any other adverse outcomes possibly related to ERCP or experimental drugs that required hospital admission or a prolonged hospital stay for further management.
arm group label: Rectal indomethacin and sublingual nitrate
arm group type: Experimental
description: All patients without contraindications should receive sublingual isosorbide dinitrate within 5 min before ERCP.
All patients without contraindications should receive rectal indomethacin within 30 min before ERCP.
arm group label: Rectal indomethacin and sublingual placebo
arm group type: Active Comparator
description: All patients without contraindications should receive sublingual placebo within 5 min before ERCP.
All patients without contraindications should receive rectal indomethacin within 30 min before ERCP.
arm group label: Rectal placebo and sublingual nitrate
arm group type: Active Comparator
description: All patients without contraindications should receive sublingual isosorbide dinitrate within 5 min before ERCP.
All patients without contraindications should receive rectal placebo within 30 min before ERCP.
arm group label: Rectal placebo and sublingual placebo
arm group type: Placebo Comparator
description: All patients without contraindications should receive sublingual placebo within 5 min before ERCP.
All patients without contraindications should receive rectal placebo within 30 min before ERCP.
intervention type: Drug
intervention name: Isosorbide Dinitrate 5 MG
description: All patients without contraindications should receive sublingual isosorbide dinitrate tablet within 5 minutes before ERCP.
arm group label: Rectal indomethacin and sublingual nitrate
arm group label: Rectal placebo and sublingual nitrate
intervention type: Drug
intervention name: Indomethacin 100 MG
description: All patients without contraindications should receive rectal indomethacin within 30 min before ERCP.
arm group label: Rectal indomethacin and sublingual nitrate
arm group label: Rectal indomethacin and sublingual placebo
intervention type: Drug
intervention name: Sublingual Placebo
description: All patients without contraindications should receive sublingual placebo within 5 minutes before ERCP.
arm group label: Rectal indomethacin and sublingual placebo
arm group label: Rectal placebo and sublingual placebo
intervention type: Drug
intervention name: Rectal placebo
description: All patients without contraindications should receive rectal placebo within 30 min before ERCP.
arm group label: Rectal placebo and sublingual nitrate
arm group label: Rectal placebo and sublingual placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
country: China
citation: Sotoudehmanesh R, Eloubeidi MA, Asgari AA, Farsinejad M, Khatibian M. A randomized trial of rectal indomethacin and sublingual nitrates to prevent post-ERCP pancreatitis. Am J Gastroenterol. 2014 Jun;109(6):903-9. doi: 10.1038/ajg.2014.9. Epub 2014 Feb 11.
PMID: 24513806
citation: Tomoda T, Kato H, Ueki T, Akimoto Y, Hata H, Fujii M, Harada R, Ogawa T, Wato M, Takatani M, Matsubara M, Kawai Y, Okada H. Combination of Diclofenac and Sublingual Nitrates Is Superior to Diclofenac Alone in Preventing Pancreatitis After Endoscopic Retrograde Cholangiopancreatography. Gastroenterology. 2019 May;156(6):1753-1760.e1. doi: 10.1053/j.gastro.2019.01.267. Epub 2019 Feb 14.
PMID: 30772342
citation: Ding J, Jin X, Pan Y, Liu S, Li Y. Glyceryl trinitrate for prevention of post-ERCP pancreatitis and improve the rate of cannulation: a meta-analysis of prospective, randomized, controlled trials. PLoS One. 2013 Oct 1;8(10):e75645. doi: 10.1371/journal.pone.0075645. eCollection 2013.
PMID: 24098392
citation: Luo H, Zhao L, Leung J, Zhang R, Liu Z, Wang X, Wang B, Nie Z, Lei T, Li X, Zhou W, Zhang L, Wang Q, Li M, Zhou Y, Liu Q, Sun H, Wang Z, Liang S, Guo X, Tao Q, Wu K, Pan Y, Guo X, Fan D. Routine pre-procedural rectal indometacin versus selective post-procedural rectal indometacin to prevent pancreatitis in patients undergoing endoscopic retrograde cholangiopancreatography: a multicentre, single-blinded, randomised controlled trial. Lancet. 2016 Jun 4;387(10035):2293-2301. doi: 10.1016/S0140-6736(16)30310-5. Epub 2016 Apr 28.
PMID: 27133971
citation: Luo H, Wang X, Zhang R, Liang S, Kang X, Zhang X, Lou Q, Xiong K, Yang J, Si L, Liu W, Liu Y, Zhou Y, Wang S, Yang M, Chen W, Han Y, Shang G, Yang X, He Y, Zou Q, Guo W, Dai Y, Zeng W, Zhu X, Gong R, Li X, Nie Z, Wang Q, Wang L, Pan Y, Guo X, Fan D. Rectal Indomethacin and Spraying of Duodenal Papilla With Epinephrine Increases Risk of Pancreatitis Following Endoscopic Retrograde Cholangiopancreatography. Clin Gastroenterol Hepatol. 2019 Jul;17(8):1597-1606.e5. doi: 10.1016/j.cgh.2018.10.043. Epub 2018 Oct 31.
PMID: 30391434
responsible party type: Principal Investigator
investigator affiliation: Air Force Military Medical University, China
investigator full name: Yanglin Pan
investigator title: Associated professor
mesh term: Pancreatitis
mesh term: Indomethacin
mesh term: Isosorbide
mesh term: Isosorbide Dinitrate
mesh term: Isosorbide-5-mononitrate
sharing ipd: Undecided