Evaluating Predictors & Interventions in Sphincter of Oddi Dysfunction (EPISOD)

A Phase III Randomized Multicenter Clinical Trial of Sphincterotomy for the Treatment of SOD III Patients

The Evaluating Predictors & Interventions in Sphincter of Oddi Dysfunction(SOD) study (EPISOD) is a randomized sham-controlled study of biliary and pancreatic sphincterotomy as treatment for patients with pain after cholecystectomy fitting the criteria for sphincter of Oddi dysfunction type III.

Study Overview

• Status: Completed
• Conditions: Sphincter of Oddi Dysfunction
• Intervention / Treatment: Procedure: ERCP with sphincterotomy; Procedure: ERCP without sphincterotomy

Detailed Description

Clinical Trial Phase: Phase III

Study Sites Seven clinical centers in US

Study Period Planned enrollment period - 3 years

Planned duration of the study - 5 years

Study Population SOD III Patients

Primary Study Objective: To ascertain whether subjects with SOD III respond to sphincterotomy,

Secondary Study Objectives

To evaluate:

• the association between the results of Sphincter of Oddi Manometry (SOM) (abnormal/normal) and the primary outcome (success/failure);
• the success rate (as defined in the primary) of subjects who receive biliary sphincterotomy alone versus subjects who receive both biliary and pancreatic sphincterotomy in the subgroup of patients with manometrically proven hypertension of the pancreatic sphincter;
• the effects of pre-specified prognostic factors on the primary outcome;
• anxiety and depression scores over time and their relation to study outcomes;
• the economic impact of SOD III, and of endoscopic sphincterotomy in patients with SOD III; and, to,
• conduct a careful follow-up study (EPISOD2) of standard of care treatment (separate protocol).

Study Design The EPISOD Trial is a parallel, randomized, double-blinded, sham-controlled, multicenter Phase III clinical trial of endoscopic sphincterotomy as treatment for adults 18 to 65 years of age diagnosed with SOD III.

Sample Size A minimum of 214 subjects will be randomized using a 2:1 allocation in favor of sphincterotomy and will be followed for 12 months post-randomization.

• Study Type: Interventional
• Enrollment (Actual): 214
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • University of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Midwest Therapeutic Endoscopy Consultants
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina Digestive Disease Center
  • Texas
    • Dallas, Texas, United States, 75203
      • Methodist Dallas Medical Center
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients diagnosed with the clinical syndrome of SOD, as defined by the Modified Functional Biliary Disorders Module of the Rome III criteria
2. Pain burden of Grade 3 or higher on RAPID Questionnaire.
3. Cholecystectomy more than 90 days before enrollment.
4. Laboratory Tests: Results of blood tests taken within 1 week preceding the baseline visit and any others available from the preceding 6 months (post-cholecystectomy):Direct bilirubin, alkaline phosphatase, amylase and lipase results must be no greater than 2 X the upper level of normal.Transaminase levels can be no more than 3 X upper limit of normal. If the transaminases are elevated (<2X ULN) in association with a pain attack, they cannot have returned to normal within 3 days.
5. Normal abdominal imaging by CT or MR/MRCP with bile duct reported at ≤9mm.
6. Upper endoscopy examination without findings to explain the pain.
7. Pain persisting despite a one trial of acid suppressant medications for one month (if tolerated).
8. Pain persisting despite a trial of antispasmodics.
9. Subjects on antidepressants for pain control (not required) should be taking them for a minimum of one month prior to the baseline assessment.

9.Patients with SOD with depressive and/or anxiety disorders who receive psychopharmacologic treatment must be on stable medication dose for at least 6 weeks.

10.Access to a telephone. 11.Must be able to speak, read, and write English. 12.Signed and dated informed consent.

Exclusion Criteria:

1. Prior ERCP treatment.
2. Age < 18 or Age > 65.
3. Pregnancy: Women who are pregnant at the time of Screening* will be excluded from the study. (*Note: Women who become pregnant AFTER the Baseline Visit/ERCP will be allowed to remain in the study for telephone follow-up visits).
4. Prior gastric resection or surgery involving biliary diversion.
5. Prior diagnosis of acute pancreatitis (lipase >3 x ULN) including post-ERCP pancreatitis, or of chronic pancreatitis by radiological imaging, EUS 5 or more criteria, or Cambridge criteria moderate or more on ERCP.
6. Daily use of prescription analgesics over the previous month.
7. Abdominal discomfort every day for the past month at level of 3 or more on a scale of 1-10.

8. Presence of significant psychiatric disorders:

   1. Lifetime psychotic disorders, bipolar disorder;
   2. Substance use disorders within 6 months;
   3. Eating disorders within 2 years
   4. Moderate & severe depression defined by BDI-II (Beck Depression Inventory) cutoff scores >22 (unless receiving stable psychiatric therapy for six weeks); and/or,
   5. Suicidal risk (equal to or greater than "low") using MINI suicide section or a score of greater than 0 on question 9 of the BDI.
9. The total number of days in the previous 3 months that the subject has taken prescription analgesics due to episodes of abdominal pain is greater than the total number of days the subject had episodes of abdominal pain.
10. Any condition that, in the investigator's opinion, makes the subject unsuitable for study participation.

ERCP Criteria:

1. Pancreas divisum (complete or partial) (known or discovered at study ERCP).
2. Any pathology found at ERCP (except sphincter hypertension).
3. Failed pancreatic manometry.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1.ERCP with sphincterotomy; ERCP with sphincterotomy: cutting the biliary sphincter muscle (sphincterotomy)	Procedure: ERCP with sphincterotomy; cutting the biliary sphincter muscle (sphincterotomy)
Placebo Comparator: 2.ERCP without sphincterotomy; ERCP without cutting the biliary sphincter muscle (sphincterotomy)	Procedure: ERCP without sphincterotomy; ERCP with sphincter manometry, but no sphincterotomy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Success	The primary outcome was a dichotomous (success/failure) variable. Success was defined as patients having a RAPID score of <6 days at months 9 and 12 post-procedure, without re-intervention and without use of prescription analgesics during months 10, 11 and 12 unless used for non-abdominal pain for no more than 14 days. The subject was considered a failure if the 12-month RAPID score was missing or collected outside the acceptable window. If the 9-month RAPID was missing, or outside of the window, then the 6-month value was used when available.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With a Successful Primary Outcome, Out of Those With Abnormal Sphincter Manometry.	Successful outcome was defined using the primary outcome definition of success at 12 months post randomization. Abnormal sphincter manometry was determined as a basal pressure of more than 40mm Hg in both leads.	1 year

Collaborators and Investigators

• Sponsor: Medical University of South Carolina
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Joseph Romagnuolo, MD, Medical Universtiy of South Carolina; Principal Investigator: Martin Freeman, MD, University of Minnesota; Principal Investigator: Richard Kozarek, MD, Virginia Mason Medical Center; Principal Investigator: Evan Fogel, MD, Indiana University; Study Chair: Peter Cotton, MD, MUSC Digestive Disease Center; Principal Investigator: Paul Tarnasky, MD, Digestive Health Associates of Texas; Principal Investigator: Giuseppe Aliperti, MD, Midwest Therapeutic Endoscopy Consultants; Principal Investigator: Priya Jamidar, MD, Yale University; Study Director: Jose Serrano, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

General Publications

• Yaghoobi M, Pauls Q, Durkalski V, Romagnuolo J, Fogel EL, Tarnasky PR, Aliperti G, Freeman ML, Kozarek RA, Jamidar PA, Wilcox CM, Elta GH, Hawes RH, Wood-Williams A, Cotton PB. Incidence and predictors of post-ERCP pancreatitis in patients with suspected sphincter of Oddi dysfunction undergoing biliary or dual sphincterotomy: results from the EPISOD prospective multicenter randomized sham-controlled study. Endoscopy. 2015 Oct;47(10):884-90. doi: 10.1055/s-0034-1392418. Epub 2015 Jul 10.
• Cotton PB, Durkalski V, Romagnuolo J, Pauls Q, Fogel E, Tarnasky P, Aliperti G, Freeman M, Kozarek R, Jamidar P, Wilcox M, Serrano J, Brawman-Mintzer O, Elta G, Mauldin P, Thornhill A, Hawes R, Wood-Williams A, Orrell K, Drossman D, Robuck P. Effect of endoscopic sphincterotomy for suspected sphincter of Oddi dysfunction on pain-related disability following cholecystectomy: the EPISOD randomized clinical trial. JAMA. 2014 May;311(20):2101-9. doi: 10.1001/jama.2014.5220.
• Romagnuolo J, Cotton PB, Durkalski V, Pauls Q, Brawman-Mintzer O, Drossman DA, Mauldin P, Orrell K, Williams AW, Fogel EL, Tarnasky PR, Aliperti G, Freeman ML, Kozarek RA, Jamidar PA, Wilcox CM, Serrano J, Elta GH. Can patient and pain characteristics predict manometric sphincter of Oddi dysfunction in patients with clinically suspected sphincter of Oddi dysfunction? Gastrointest Endosc. 2014 May;79(5):765-72. doi: 10.1016/j.gie.2013.11.037. Epub 2014 Jan 25.
• Cotton PB, Durkalski V, Orrell KB, Brawman-Mintzer O, Drossman DA, Wilcox CM, Mauldin PD, Elta GH, Tarnasky PR, Fogel EL, Jagganath SB, Kozarek RA, Freeman ML, Romagnuolo J, Robuck PR. Challenges in planning and initiating a randomized clinical study of sphincter of Oddi dysfunction. Gastrointest Endosc. 2010 Nov;72(5):986-91. doi: 10.1016/j.gie.2010.08.022.

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: May 30, 2008
• First Submitted That Met QC Criteria: May 30, 2008
• First Posted (Estimate): June 3, 2008

Study Record Updates

• Last Update Posted (Actual): April 19, 2018
• Last Update Submitted That Met QC Criteria: March 20, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Sphincter of Oddi Dysfunction; Sphincterotomy; Pancreatitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Biliary Tract Diseases; Bile Duct Diseases; Biliary Dyskinesia; Common Bile Duct Diseases; Sphincter of Oddi Dysfunction
• Other Study ID Numbers: DK074739; U01DK074739 (U.S. NIH Grant/Contract)