<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/NCT02197338</url>
  </required_header>
  <id_info>
    <org_study_id>Biliary Cannulation Trial</org_study_id>
    <nct_id>NCT02197338</nct_id>
  </id_info>
  <brief_title>Randomized Trial of Wire and Sphincterotome Systems for Biliary Cannulation</brief_title>
  <official_title>Randomized Controlled Trial of Short Versus Long Wire and Small Versus Standard Sphincterotomes for Initial Biliary Cannulation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Southern California</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Southern California</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      1. Cannulation of (placement of a small catheter into) the bile duct is critical to remove&#xD;
           bile duct stones, divert bile leaks, and decompress biliary obstruction due to cancer.&#xD;
&#xD;
        2. Given the small size of the bile duct orifice and its close proximity to the pancreatic&#xD;
           duct, selective biliary cannulation is the most difficult part of the endoscopic&#xD;
           retrograde cholangiography (ERCP).&#xD;
&#xD;
        3. New small diameter sphincteromes and &quot;short wire&quot; systems (which allow physicians to&#xD;
           control guidewires) offer potential, though untested advantages.&#xD;
&#xD;
        4. At most hosptial both the long and short wire systems as well as small versus standard&#xD;
           are routinely used for clinical care.&#xD;
&#xD;
        5. Our hypothesis is that small diameter, physician controlled wires favor biliary&#xD;
           cannulation&#xD;
&#xD;
        6. Our objective will be to assess whether small diameter sphincterotomes and &quot;short wire&quot;&#xD;
           physician controlled guidewire cannulation favors successful bile duct cannulation and&#xD;
           minimize complications.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1.0 BACKGROUND&#xD;
&#xD;
      Bile duct access is the most difficult part of endoscopic retrograde cholangiography (ERCP)&#xD;
      performed for the biliary indications of bile duct stones, leak, and stricture. In the past&#xD;
      decade there has been an evolution in the technology and approach used to achieve selective&#xD;
      biliary cannulation, In the classic approach a standard cannula is placed into the biliary&#xD;
      orifice and contrast injected to confirm placement. Subsequently, a long wire is passed by&#xD;
      the assistant deeply into the duct and the cannulatome exchange for a sphincterotome which is&#xD;
      used to perform papillotomy.&#xD;
&#xD;
      The first major change in cannulation approach has been the widespread use of the&#xD;
      sphincterotome to obtain initial biliary access in lieu of the cannulatome. This is in part&#xD;
      driven by economics. With the advent of endoscopic ultrasound (EUS) and magnetic resonance&#xD;
      cholangiopancreatography (MRCP) almost all ERCP is therapeutic and sphincterotomy is&#xD;
      typically part of this approach.1 Thus it is sensible to forgo the step of using the&#xD;
      cannulatome which enables only diagnostic ERCP. In addition to cutting, the wire on the&#xD;
      distal tip of the sphincterotome enables variable flexion in the direction of the bile duct,&#xD;
      a feature lacking for the cannulatome.&#xD;
&#xD;
      Additionally, high quality comparison trials suggest that the sphincterotome is superior to&#xD;
      the cannulatome for initial access. Schwacha et al prospectively randomized patients to bile&#xD;
      duct cannulation with the standard cannulatome versus the sphincterotome.2 After five&#xD;
      attempts bile duct access was achieved in 62% of those in the standard catheter group&#xD;
      compared to 84% in the sphincterotome group. Cortus et al randomized patients to &lt;15 attempts&#xD;
      to access with bile duct with the cannulatome versus the sphincterotome and found that&#xD;
      initial biliary access was obtained in 67% in the former versus 97% in the latter groups.3 In&#xD;
      addition the mean number of cannulation attempts and time to achieve selective biliary&#xD;
      cannulation was also less in the sphincterotome group. Given these considerations most&#xD;
      American endoscopists use sphincterotomes for initial biliary cannulation.4&#xD;
&#xD;
      Most modern sphincterotomes have two to three lumens to enable simulatenous passage of&#xD;
      contrast and wire into the bile duct. Traditionally, contrast was first injected to confirm&#xD;
      that the bile duct as opposed to the pancreatic duct had been accessed. In 2004 Lella&#xD;
      randomized 400 patients to the standard approach of contrast injection versus the passage of&#xD;
      the guidewire to confirm bile duct cannulation.5 In the contrast group 4% of patients&#xD;
      developed pancreatitis compared to none in the wire guided group and high pancreatic enzyme&#xD;
      levels (5 times the upper limit of normal) developed in 20% of contrast guided versus 5% of&#xD;
      wire guided cases. Subsequent large randomized trials have consistently demonstrated post&#xD;
      ERCP pancreatitis rates of 2-9% in wire guided versus 10-17% in contrast guided ERCP.6-7 Wire&#xD;
      guided cannulation has also been shown to shorten cannulation and fluoroscopy times.8&#xD;
&#xD;
      1.2 Additionally, several new technologies have been introduced with potential but unproven&#xD;
      advantages. Traditionally the ERCP wires have been as long as the combination of the scope&#xD;
      channel and accessory length such that an assistant could control placement during the&#xD;
      procedure. Recently, short wire system have been developed in which wires may be stripped out&#xD;
      of catheters with tear away lumens down to the distal most aspect (5-50cm) depending on the&#xD;
      accessory.9 A stripped down sphincterotome accomodates a short wire which can be completely&#xD;
      controlled by the endoscopist enabling physician controlled wire passage. A locking device on&#xD;
      the scope allows the short wire to be fixed reliably during therapeutic maneuvers. The&#xD;
      advantage of the short wire system is that it decreases reliance on an assistant. The&#xD;
      disadvantage is that is may decrease the backpressure on the sphincterotome which may be&#xD;
      achieved based on Newton's third law (pulling the wire back helps advance the tome forward).&#xD;
&#xD;
      There has been little published work comparing short wire to traditional long wire systems.&#xD;
      Available data suggests trends toward shorter fluoroscopy and procedure times.10&#xD;
      Additionally, the short wire system appears to enable shorter time to bile duct system&#xD;
      placement compared to the long wire system. A recent national survey revealed that 43% of&#xD;
      endoscopists favored the short wire system compared to 33% the long wire system.4&#xD;
&#xD;
      1.3 An additional technology frequently used to facilitate cannulation are smaller sized&#xD;
      sphincterotomes. Theoretically, these small diameter tomes may enable access into bile duct&#xD;
      with more diminutive orifices. One small randomized trial compared standard 5Fr tomes to 4Fr&#xD;
      tomes. Cannulation in both groups was 84% though the study was prematurely terminated.11&#xD;
&#xD;
      In patients in whom biliary access is still not achieved often another type of sphincterotome&#xD;
      or cannulatome will be used. If this does not work a wire or pancreatic stent will often be&#xD;
      placed in the pancreatic duct ideally to change the orientation of the papilla in a favorable&#xD;
      way.12 The latter strategy will also decrease the risk of post ERCP pancreatitis in difficult&#xD;
      cases including those who have undergone multiple cannulation attempts.13 If these approaches&#xD;
      fail an access or precut papillotomy may be performed using a needle knife. Precut&#xD;
      sphincterotomy in the direction of the bile duct can either be performed from the orifice&#xD;
      (gough) or above the orifice (fistulotomy).12, 14&#xD;
&#xD;
      Currently both the small and standard tomes are routinely used at LAC. The Rx System can be&#xD;
      converted from long to short wire method using the same device. Both long and short wire&#xD;
      approaches are routinely performed at LAC. There is no standardized approach.&#xD;
&#xD;
      2.0 OBJECTIVES AND PURPOSE&#xD;
&#xD;
      To assess whether initial bile duct cannulation with a 39Fr versus 44Fr sphincterotomes and&#xD;
      the long verus short wire systems favors successful bile duct cannulation and minimizes&#xD;
      complications. This will help to developed an evidence based approach to initial bile duct&#xD;
      access during endoscopic retrograde cholangiopancreatography (ERCP).&#xD;
&#xD;
      3.0 STUDY DESIGN: The study will be a prospective randomized controlled trial. All patients&#xD;
      undergoing ERCP for standard indication including stones, leaks or jaundice will be eligible.&#xD;
      Those who have undergone prior sphincterotomy, which ensures biliary access will be excluded.&#xD;
      Additionally those with prior ERCP and failed bile duct cannulation will be excluded.&#xD;
      Additionally, patients who require ERCP only for pancreatic indications such as pancreatic&#xD;
      duct leak will be exlcluded as bile duct cannulation is not required for clinical&#xD;
      indications.&#xD;
&#xD;
      Patients will be randomized using a 2 x 2 factorial design to initial cannulation attempt&#xD;
      with a small versus standard sphincterotome (1:1) and short versus long wire system (1:1).&#xD;
      The Rx Biliary System (Boston Scientific; Natick, MA) will be used. In those randomized to&#xD;
      the short wire approach, the wire will be stripped from the tear away lumen to convert from a&#xD;
      long to short wire system. The wire will be controlled by the endoscopist &quot;physician&#xD;
      controlled.&quot; In those randomized to the long wire approach the long wire will be left in the&#xD;
      lumen which will not be stripped down. The wire will be controlled by the assistant. Those&#xD;
      randomized to the small sized tome will initially use the 39Fr tome and those randomized to&#xD;
      the standard tome will use the 44Fr tome.&#xD;
&#xD;
      In all 4 groups initial successful cannulation will be defined as the acquisition of deep&#xD;
      bile duct access within the first 8 attempts. An attempt is defined as the placement of the&#xD;
      cannula into the biliary orifice followed by advancement of the wire or contrast injection.&#xD;
&#xD;
      At LAC+USC procedures are performed by 2-3 third year fellows who are recognized as&#xD;
      clinically and technically excellent. Fellows at other levels; first year and second year&#xD;
      fellows are not allowed to perform ERCP. All procedures are directly supervised by a faculty&#xD;
      physician who takes over cannulation if the fellow is not successfully after 3-5 attempts.&#xD;
      Faculty physicans perform the procedures alone only under rare circumstances. However, to&#xD;
      account for this possibility randomization will be stratified by 3rd fellow+faculty and&#xD;
      faculty alone.&#xD;
&#xD;
      To account for variability of assistants we will make certain that the policy that nursing&#xD;
      assistants rotate on monthly basis is enforced which will ensure an even distribution of&#xD;
      technical assistance which reflects the real word scenario.&#xD;
&#xD;
      If biliary cannulation is not achieved after 8 attempts any wire system or sphincterotome&#xD;
      size may be used at the discretion of the attending endoscopist. Thus the assigned tome and&#xD;
      wire approach may be abandoned or continued at the discretion of the faculty member&#xD;
      performing the case. Additionally, pancreatic wire or stent placement or precut&#xD;
      sphincterotomy will be performed at the discretion of the attending endoscopist.&#xD;
&#xD;
      The primary outcome will be successful initial bile duct cannulation as defined by&#xD;
      cannulation with the assigned technology within the first 8 attempts.&#xD;
&#xD;
      The secondary outcomes will include total cannulation and fluoroscopy times, inadvertent,&#xD;
      pancreatic duct access, and ERCP complications&#xD;
&#xD;
      All patients who are inpatient will be seen in follow-up on the second procedure day and data&#xD;
      to assess for outcomes will be collected by the study team. They will be called 7 days after&#xD;
      the procedure. Those who are discharged on the day of the procedure will be called 1 day&#xD;
      after the procedure and 7 days after the procedure to assess for these outcomes. Thus all&#xD;
      patients will be assessed either with a follow up visist or phone call at 1 and 7 days post&#xD;
      procedure.&#xD;
&#xD;
      4.0 STATISTICAL CONSIDERATONS:&#xD;
&#xD;
      A 2 x 2 factorial design will be used with a 1:1 randomization to 44Fr versus 39Fr tome and&#xD;
      1:1 randomization to long or short wire system.&#xD;
&#xD;
      Our a priori hypothesis is that there will be a 10% difference in successful initial&#xD;
      cannulation (85% to 95%). At an alpha of 0.05 and beta of 0.10 a sample size of 498 will be&#xD;
      needed to demonstrate a difference.&#xD;
&#xD;
      A planned interim analysis will be performed after 200 patients have been enrolled.&#xD;
&#xD;
      The rule for stopping are as follows;&#xD;
&#xD;
      A) If significant difference in the primary outcome (cannulation within 8 attempts) is&#xD;
      reached in one arm (wire length or cannulatome size) that arm will be stopped. An interim&#xD;
      test of the effect of administration will be computed to determine the sample size for the&#xD;
      remaining arm with a 2 group design moving forward.&#xD;
&#xD;
      B) If both a superior wire length and cannulatome size strategy (both arms) are demonstrated&#xD;
      after 200 cases the trial will be stopped and reported.&#xD;
&#xD;
      C) If significance is reached in neither arm at 200 cases, then the 4 groups will continue&#xD;
      until the sample size of 500 is reached.&#xD;
&#xD;
      D) If significantly more complications including pancreatitis, perforation, bleeding,&#xD;
      cholangitis are seen in one arm (wire length or cannulatome size) that arm will be stopped.&#xD;
&#xD;
      Dichotomous outcomes will be compared using a Fischer's exact or chi squared test and&#xD;
      continuous outcomes will be compared using a Wilcoxan rank sum test.&#xD;
&#xD;
      Statistical analyses will be performed by biostatisticians at the Biostatistical and&#xD;
      Bioinformatics Resource Group within the SC CTSI.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>April 2016</start_date>
  <completion_date type="Actual">April 2016</completion_date>
  <primary_completion_date type="Actual">April 2016</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>Factorial Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Bile Duct Cannulation</measure>
    <time_frame>1 year</time_frame>
    <description>The primary outcome is successful initial cannulation as defined by bile duct with the assigned technology (ie size of cannulatome and type of wire system) within the first 8 attempts. The rates of cannulation among the 4 groups will be compared.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Cannulation Attempts</measure>
    <time_frame>1 Year</time_frame>
    <description>Total number of cannulation attempts to gain bile duct access.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Post ERCP Pancreatitis</measure>
    <time_frame>1 year</time_frame>
    <description>Post ERCP pancreatitis defined as two of three of the following; post procedure pain &gt;3 on the visual analogue scale, imaging imaging consistent with acute pancreatitis, and amylase &gt;3 ULN sustained x 48 hours</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Number of times wire is passed into PD</measure>
    <time_frame>1 year</time_frame>
    <description>Number of times wire is passed into PD</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of times PD is opacified with contrast</measure>
    <time_frame>1 year</time_frame>
    <description>Number of times PD is opacified with contrast</description>
  </other_outcome>
  <other_outcome>
    <measure>Fluoroscopy time (seconds).</measure>
    <time_frame>1 year</time_frame>
    <description>Fluoroscopy time (seconds).</description>
  </other_outcome>
  <other_outcome>
    <measure>Cannulation time which will be defined as the time from scope positioning in second portion of duodenum to cannulation (minutes).</measure>
    <time_frame>1 year</time_frame>
    <description>Cannulation time which will be defined as the time from scope positioning in second portion of duodenum to cannulation (minutes).</description>
  </other_outcome>
  <other_outcome>
    <measure>Total procedure time (minutes</measure>
    <time_frame>1 year</time_frame>
    <description>Total procedure time (minutes</description>
  </other_outcome>
  <other_outcome>
    <measure>Post ERCP cholangitis defined as fever, pain, and abnormal liver function tests</measure>
    <time_frame>1 year</time_frame>
    <description>Post ERCP cholangitis defined as fever, pain, and abnormal liver function tests</description>
  </other_outcome>
  <other_outcome>
    <measure>Perforation of the bowel or bile duct</measure>
    <time_frame>1 year</time_frame>
    <description>Perforation of the bowel or bile duct</description>
  </other_outcome>
  <other_outcome>
    <measure>Bleeding during or immediately after the procedure related to ERCP</measure>
    <time_frame>1 year</time_frame>
    <description>Bleeding during or immediately after the procedure related to ERCP</description>
  </other_outcome>
  <other_outcome>
    <measure>Precut sphincterotomy needed for biliary access</measure>
    <time_frame>1 year</time_frame>
    <description>Precut sphincterotomy needed for biliary access</description>
  </other_outcome>
  <other_outcome>
    <measure>Pancreas stent placement felt to be necessary</measure>
    <time_frame>1 year</time_frame>
    <description>Pancreas stent placement felt to be necessary</description>
  </other_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">498</enrollment>
  <condition>Cholestasis, Extrahepatic</condition>
  <arm_group>
    <arm_group_label>Short Wire, Small Tome</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Short wire system, small sized sphincterotome will be used to perform the Intervention of Bile Duct Cannulation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Short Wire, Standard Tome</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Short wire system, standard sized sphincterotome will be used to perform the Intervention of Bile Duct Cannulation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Long Wire, Small Tome</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Long wire system, small sized sphincterotome will be used to perform the Intervention of Bile Duct Cannulation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Long Wire, Standard Tome</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Long wire system, standard sized sphincterotome will be used to perform the Intervention of Bile Duct Cannulation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Bile Duct Cannulation</intervention_name>
    <description>Initial bile duct cannulation (first 8 attempts) will be made in each subject using one of the four cannulation strategies described in the 4 arms. The arm for each subject will be assigned by randomziation.</description>
    <arm_group_label>Long Wire, Small Tome</arm_group_label>
    <arm_group_label>Long Wire, Standard Tome</arm_group_label>
    <arm_group_label>Short Wire, Small Tome</arm_group_label>
    <arm_group_label>Short Wire, Standard Tome</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Undergoing ERCP at LAC+USC Medical Centers for standard indications including bile&#xD;
             duct stones, bile leak, and biliary obstruction will be included.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Prior ERCP with sphincterotomy&#xD;
&#xD;
          2. Prior ERCP with failed bile duct cannulation&#xD;
&#xD;
          3. Pregnant, imprisoned, under age 18, unable to give informed consent&#xD;
&#xD;
          4. Prior biliary diversion surgery will be excluded&#xD;
&#xD;
          5. Those who require ERCP only for pancreatic duct indications will also be excluded as&#xD;
             bile duct cannulation is not clinically necessary in this group&#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>James Buxbaum, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Southern California</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Los Angeles County Hospital</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Kawakami H, Maguchi H, Mukai T, Hayashi T, Sasaki T, Isayama H, Nakai Y, Yasuda I, Irisawa A, Niido T, Okabe Y, Ryozawa S, Itoi T, Hanada K, Kikuyama M, Arisaka Y, Kikuchi S; Japan Bile Duct Cannulation Study Group. A multicenter, prospective, randomized study of selective bile duct cannulation performed by multiple endoscopists: the BIDMEN study. Gastrointest Endosc. 2012 Feb;75(2):362-72, 372.e1. doi: 10.1016/j.gie.2011.10.012.</citation>
    <PMID>22248605</PMID>
  </results_reference>
  <results_reference>
    <citation>Draganov PV, Kowalczyk L, Fazel A, Moezardalan K, Pan JJ, Forsmark CE. Prospective randomized blinded comparison of a short-wire endoscopic retrograde cholangiopancreatography system with traditional long-wire devices. Dig Dis Sci. 2010 Feb;55(2):510-5. doi: 10.1007/s10620-009-1052-5.</citation>
    <PMID>19957034</PMID>
  </results_reference>
  <results_reference>
    <citation>Abraham NS, Williams SP, Thompson K, Love JR, MacIntosh DG. 5F sphincterotomes and 4F sphincterotomes are equivalent for the selective cannulation of the common bile duct. Gastrointest Endosc. 2006 Apr;63(4):615-21. doi: 10.1016/j.gie.2005.10.041.</citation>
    <PMID>16564862</PMID>
  </results_reference>
  <results_reference>
    <citation>Freeman ML, Guda NM. ERCP cannulation: a review of reported techniques. Gastrointest Endosc. 2005 Jan;61(1):112-25. doi: 10.1016/s0016-5107(04)02463-0. No abstract available.</citation>
    <PMID>15672074</PMID>
  </results_reference>
  <verification_date>April 2016</verification_date>
  <study_first_submitted>July 18, 2014</study_first_submitted>
  <study_first_submitted_qc>July 18, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 22, 2014</study_first_posted>
  <last_update_submitted>April 13, 2016</last_update_submitted>
  <last_update_submitted_qc>April 13, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">April 15, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Southern California</investigator_affiliation>
    <investigator_full_name>James Buxbaum</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>cholangiopancreatography, endoscopic retrograde</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cholestasis</mesh_term>
    <mesh_term>Cholestasis, Extrahepatic</mesh_term>
  </condition_browse>
  <!-- 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/NCT02197338
org study id: Biliary Cannulation Trial
nct id: NCT02197338
lead sponsor: 
has dmc: Yes
1. Cannulation of (placement of a small catheter into) the bile duct is critical to remove
           bile duct stones, divert bile leaks, and decompress biliary obstruction due to cancer.

        2. Given the small size of the bile duct orifice and its close proximity to the pancreatic
           duct, selective biliary cannulation is the most difficult part of the endoscopic
           retrograde cholangiography (ERCP).

        3. New small diameter sphincteromes and "short wire" systems (which allow physicians to
           control guidewires) offer potential, though untested advantages.

        4. At most hosptial both the long and short wire systems as well as small versus standard
           are routinely used for clinical care.

        5. Our hypothesis is that small diameter, physician controlled wires favor biliary
           cannulation

        6. Our objective will be to assess whether small diameter sphincterotomes and "short wire"
           physician controlled guidewire cannulation favors successful bile duct cannulation and
           minimize complications.
1.0 BACKGROUND

      Bile duct access is the most difficult part of endoscopic retrograde cholangiography (ERCP)
      performed for the biliary indications of bile duct stones, leak, and stricture. In the past
      decade there has been an evolution in the technology and approach used to achieve selective
      biliary cannulation, In the classic approach a standard cannula is placed into the biliary
      orifice and contrast injected to confirm placement. Subsequently, a long wire is passed by
      the assistant deeply into the duct and the cannulatome exchange for a sphincterotome which is
      used to perform papillotomy.

      The first major change in cannulation approach has been the widespread use of the
      sphincterotome to obtain initial biliary access in lieu of the cannulatome. This is in part
      driven by economics. With the advent of endoscopic ultrasound (EUS) and magnetic resonance
      cholangiopancreatography (MRCP) almost all ERCP is therapeutic and sphincterotomy is
      typically part of this approach.1 Thus it is sensible to forgo the step of using the
      cannulatome which enables only diagnostic ERCP. In addition to cutting, the wire on the
      distal tip of the sphincterotome enables variable flexion in the direction of the bile duct,
      a feature lacking for the cannulatome.

      Additionally, high quality comparison trials suggest that the sphincterotome is superior to
      the cannulatome for initial access. Schwacha et al prospectively randomized patients to bile
      duct cannulation with the standard cannulatome versus the sphincterotome.2 After five
      attempts bile duct access was achieved in 62% of those in the standard catheter group
      compared to 84% in the sphincterotome group. Cortus et al randomized patients to <15 attempts
      to access with bile duct with the cannulatome versus the sphincterotome and found that
      initial biliary access was obtained in 67% in the former versus 97% in the latter groups.3 In
      addition the mean number of cannulation attempts and time to achieve selective biliary
      cannulation was also less in the sphincterotome group. Given these considerations most
      American endoscopists use sphincterotomes for initial biliary cannulation.4

      Most modern sphincterotomes have two to three lumens to enable simulatenous passage of
      contrast and wire into the bile duct. Traditionally, contrast was first injected to confirm
      that the bile duct as opposed to the pancreatic duct had been accessed. In 2004 Lella
      randomized 400 patients to the standard approach of contrast injection versus the passage of
      the guidewire to confirm bile duct cannulation.5 In the contrast group 4% of patients
      developed pancreatitis compared to none in the wire guided group and high pancreatic enzyme
      levels (5 times the upper limit of normal) developed in 20% of contrast guided versus 5% of
      wire guided cases. Subsequent large randomized trials have consistently demonstrated post
      ERCP pancreatitis rates of 2-9% in wire guided versus 10-17% in contrast guided ERCP.6-7 Wire
      guided cannulation has also been shown to shorten cannulation and fluoroscopy times.8

      1.2 Additionally, several new technologies have been introduced with potential but unproven
      advantages. Traditionally the ERCP wires have been as long as the combination of the scope
      channel and accessory length such that an assistant could control placement during the
      procedure. Recently, short wire system have been developed in which wires may be stripped out
      of catheters with tear away lumens down to the distal most aspect (5-50cm) depending on the
      accessory.9 A stripped down sphincterotome accomodates a short wire which can be completely
      controlled by the endoscopist enabling physician controlled wire passage. A locking device on
      the scope allows the short wire to be fixed reliably during therapeutic maneuvers. The
      advantage of the short wire system is that it decreases reliance on an assistant. The
      disadvantage is that is may decrease the backpressure on the sphincterotome which may be
      achieved based on Newton's third law (pulling the wire back helps advance the tome forward).

      There has been little published work comparing short wire to traditional long wire systems.
      Available data suggests trends toward shorter fluoroscopy and procedure times.10
      Additionally, the short wire system appears to enable shorter time to bile duct system
      placement compared to the long wire system. A recent national survey revealed that 43% of
      endoscopists favored the short wire system compared to 33% the long wire system.4

      1.3 An additional technology frequently used to facilitate cannulation are smaller sized
      sphincterotomes. Theoretically, these small diameter tomes may enable access into bile duct
      with more diminutive orifices. One small randomized trial compared standard 5Fr tomes to 4Fr
      tomes. Cannulation in both groups was 84% though the study was prematurely terminated.11

      In patients in whom biliary access is still not achieved often another type of sphincterotome
      or cannulatome will be used. If this does not work a wire or pancreatic stent will often be
      placed in the pancreatic duct ideally to change the orientation of the papilla in a favorable
      way.12 The latter strategy will also decrease the risk of post ERCP pancreatitis in difficult
      cases including those who have undergone multiple cannulation attempts.13 If these approaches
      fail an access or precut papillotomy may be performed using a needle knife. Precut
      sphincterotomy in the direction of the bile duct can either be performed from the orifice
      (gough) or above the orifice (fistulotomy).12, 14

      Currently both the small and standard tomes are routinely used at LAC. The Rx System can be
      converted from long to short wire method using the same device. Both long and short wire
      approaches are routinely performed at LAC. There is no standardized approach.

      2.0 OBJECTIVES AND PURPOSE

      To assess whether initial bile duct cannulation with a 39Fr versus 44Fr sphincterotomes and
      the long verus short wire systems favors successful bile duct cannulation and minimizes
      complications. This will help to developed an evidence based approach to initial bile duct
      access during endoscopic retrograde cholangiopancreatography (ERCP).

      3.0 STUDY DESIGN: The study will be a prospective randomized controlled trial. All patients
      undergoing ERCP for standard indication including stones, leaks or jaundice will be eligible.
      Those who have undergone prior sphincterotomy, which ensures biliary access will be excluded.
      Additionally those with prior ERCP and failed bile duct cannulation will be excluded.
      Additionally, patients who require ERCP only for pancreatic indications such as pancreatic
      duct leak will be exlcluded as bile duct cannulation is not required for clinical
      indications.

      Patients will be randomized using a 2 x 2 factorial design to initial cannulation attempt
      with a small versus standard sphincterotome (1:1) and short versus long wire system (1:1).
      The Rx Biliary System (Boston Scientific; Natick, MA) will be used. In those randomized to
      the short wire approach, the wire will be stripped from the tear away lumen to convert from a
      long to short wire system. The wire will be controlled by the endoscopist "physician
      controlled." In those randomized to the long wire approach the long wire will be left in the
      lumen which will not be stripped down. The wire will be controlled by the assistant. Those
      randomized to the small sized tome will initially use the 39Fr tome and those randomized to
      the standard tome will use the 44Fr tome.

      In all 4 groups initial successful cannulation will be defined as the acquisition of deep
      bile duct access within the first 8 attempts. An attempt is defined as the placement of the
      cannula into the biliary orifice followed by advancement of the wire or contrast injection.

      At LAC+USC procedures are performed by 2-3 third year fellows who are recognized as
      clinically and technically excellent. Fellows at other levels; first year and second year
      fellows are not allowed to perform ERCP. All procedures are directly supervised by a faculty
      physician who takes over cannulation if the fellow is not successfully after 3-5 attempts.
      Faculty physicans perform the procedures alone only under rare circumstances. However, to
      account for this possibility randomization will be stratified by 3rd fellow+faculty and
      faculty alone.

      To account for variability of assistants we will make certain that the policy that nursing
      assistants rotate on monthly basis is enforced which will ensure an even distribution of
      technical assistance which reflects the real word scenario.

      If biliary cannulation is not achieved after 8 attempts any wire system or sphincterotome
      size may be used at the discretion of the attending endoscopist. Thus the assigned tome and
      wire approach may be abandoned or continued at the discretion of the faculty member
      performing the case. Additionally, pancreatic wire or stent placement or precut
      sphincterotomy will be performed at the discretion of the attending endoscopist.

      The primary outcome will be successful initial bile duct cannulation as defined by
      cannulation with the assigned technology within the first 8 attempts.

      The secondary outcomes will include total cannulation and fluoroscopy times, inadvertent,
      pancreatic duct access, and ERCP complications

      All patients who are inpatient will be seen in follow-up on the second procedure day and data
      to assess for outcomes will be collected by the study team. They will be called 7 days after
      the procedure. Those who are discharged on the day of the procedure will be called 1 day
      after the procedure and 7 days after the procedure to assess for these outcomes. Thus all
      patients will be assessed either with a follow up visist or phone call at 1 and 7 days post
      procedure.

      4.0 STATISTICAL CONSIDERATONS:

      A 2 x 2 factorial design will be used with a 1:1 randomization to 44Fr versus 39Fr tome and
      1:1 randomization to long or short wire system.

      Our a priori hypothesis is that there will be a 10% difference in successful initial
      cannulation (85% to 95%). At an alpha of 0.05 and beta of 0.10 a sample size of 498 will be
      needed to demonstrate a difference.

      A planned interim analysis will be performed after 200 patients have been enrolled.

      The rule for stopping are as follows;

      A) If significant difference in the primary outcome (cannulation within 8 attempts) is
      reached in one arm (wire length or cannulatome size) that arm will be stopped. An interim
      test of the effect of administration will be computed to determine the sample size for the
      remaining arm with a 2 group design moving forward.

      B) If both a superior wire length and cannulatome size strategy (both arms) are demonstrated
      after 200 cases the trial will be stopped and reported.

      C) If significance is reached in neither arm at 200 cases, then the 4 groups will continue
      until the sample size of 500 is reached.

      D) If significantly more complications including pancreatitis, perforation, bleeding,
      cholangitis are seen in one arm (wire length or cannulatome size) that arm will be stopped.

      Dichotomous outcomes will be compared using a Fischer's exact or chi squared test and
      continuous outcomes will be compared using a Wilcoxan rank sum test.

      Statistical analyses will be performed by biostatisticians at the Biostatistical and
      Bioinformatics Resource Group within the SC CTSI.
allocation: Randomized
intervention model: Factorial Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Bile Duct Cannulation
time frame: 1 year
description: The primary outcome is successful initial cannulation as defined by bile duct with the assigned technology (ie size of cannulatome and type of wire system) within the first 8 attempts. The rates of cannulation among the 4 groups will be compared.
measure: Number of Cannulation Attempts
time frame: 1 Year
description: Total number of cannulation attempts to gain bile duct access.
measure: Post ERCP Pancreatitis
time frame: 1 year
description: Post ERCP pancreatitis defined as two of three of the following; post procedure pain >3 on the visual analogue scale, imaging imaging consistent with acute pancreatitis, and amylase >3 ULN sustained x 48 hours
measure: Number of times wire is passed into PD
time frame: 1 year
description: Number of times wire is passed into PD
measure: Number of times PD is opacified with contrast
time frame: 1 year
description: Number of times PD is opacified with contrast
measure: Fluoroscopy time (seconds).
time frame: 1 year
description: Fluoroscopy time (seconds).
measure: Cannulation time which will be defined as the time from scope positioning in second portion of duodenum to cannulation (minutes).
time frame: 1 year
description: Cannulation time which will be defined as the time from scope positioning in second portion of duodenum to cannulation (minutes).
measure: Total procedure time (minutes
time frame: 1 year
description: Total procedure time (minutes
measure: Post ERCP cholangitis defined as fever, pain, and abnormal liver function tests
time frame: 1 year
description: Post ERCP cholangitis defined as fever, pain, and abnormal liver function tests
measure: Perforation of the bowel or bile duct
time frame: 1 year
description: Perforation of the bowel or bile duct
measure: Bleeding during or immediately after the procedure related to ERCP
time frame: 1 year
description: Bleeding during or immediately after the procedure related to ERCP
measure: Precut sphincterotomy needed for biliary access
time frame: 1 year
description: Precut sphincterotomy needed for biliary access
measure: Pancreas stent placement felt to be necessary
time frame: 1 year
description: Pancreas stent placement felt to be necessary
arm group label: Short Wire, Small Tome
arm group type: Experimental
description: Short wire system, small sized sphincterotome will be used to perform the Intervention of Bile Duct Cannulation.
arm group label: Short Wire, Standard Tome
arm group type: Active Comparator
description: Short wire system, standard sized sphincterotome will be used to perform the Intervention of Bile Duct Cannulation.
arm group label: Long Wire, Small Tome
arm group type: Active Comparator
description: Long wire system, small sized sphincterotome will be used to perform the Intervention of Bile Duct Cannulation.
arm group label: Long Wire, Standard Tome
arm group type: Active Comparator
description: Long wire system, standard sized sphincterotome will be used to perform the Intervention of Bile Duct Cannulation.
intervention type: Other
intervention name: Bile Duct Cannulation
description: Initial bile duct cannulation (first 8 attempts) will be made in each subject using one of the four cannulation strategies described in the 4 arms. The arm for each subject will be assigned by randomziation.
arm group label: Long Wire, Small Tome
arm group label: Long Wire, Standard Tome
arm group label: Short Wire, Small Tome
arm group label: Short Wire, Standard Tome
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: James Buxbaum, MD
role: Principal Investigator
affiliation: University of Southern California
facility: 
country: United States
citation: Kawakami H, Maguchi H, Mukai T, Hayashi T, Sasaki T, Isayama H, Nakai Y, Yasuda I, Irisawa A, Niido T, Okabe Y, Ryozawa S, Itoi T, Hanada K, Kikuyama M, Arisaka Y, Kikuchi S; Japan Bile Duct Cannulation Study Group. A multicenter, prospective, randomized study of selective bile duct cannulation performed by multiple endoscopists: the BIDMEN study. Gastrointest Endosc. 2012 Feb;75(2):362-72, 372.e1. doi: 10.1016/j.gie.2011.10.012.
PMID: 22248605
citation: Draganov PV, Kowalczyk L, Fazel A, Moezardalan K, Pan JJ, Forsmark CE. Prospective randomized blinded comparison of a short-wire endoscopic retrograde cholangiopancreatography system with traditional long-wire devices. Dig Dis Sci. 2010 Feb;55(2):510-5. doi: 10.1007/s10620-009-1052-5.
PMID: 19957034
citation: Abraham NS, Williams SP, Thompson K, Love JR, MacIntosh DG. 5F sphincterotomes and 4F sphincterotomes are equivalent for the selective cannulation of the common bile duct. Gastrointest Endosc. 2006 Apr;63(4):615-21. doi: 10.1016/j.gie.2005.10.041.
PMID: 16564862
citation: Freeman ML, Guda NM. ERCP cannulation: a review of reported techniques. Gastrointest Endosc. 2005 Jan;61(1):112-25. doi: 10.1016/s0016-5107(04)02463-0. No abstract available.
PMID: 15672074
responsible party type: Principal Investigator
investigator affiliation: University of Southern California
investigator full name: James Buxbaum
investigator title: Assistant Professor
mesh term: Cholestasis
mesh term: Cholestasis, Extrahepatic