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

Protocol Title:Evaluating Predictors & Interventions in Sphincter of Oddi Dysfunction(SOD) Acronym EPISOD

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 two-arm 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.

• Procedure: Pancreatic Sphincterotomy
  cutting the sphincter muscle (sphincterotomy)
• Procedure: Pancreatic and Biliary Sphincterotomy
  cutting the sphincter muscle (sphincterotomy)
• Procedure: ERCP
  ERCP Procedure: For the procedure, you will lie on your left side on an examining table in an x-ray room. You will be given medication to help numb the back of your throat and a sedative or anesthetic to help you relax during the exam. The physician will guide the scope through your esophagus, stomach, and duodenum until it reaches the spot where the ducts of the biliary tree and pancreas open into the duodenum. The physician will the pass a small plastic tube through the scope. Through the tube, the physician will inject a dye into the ducts to make them show up clearly on x rays. X rays are taken as soon as the dye is injected

• Active Comparator: 1
  Pancreatic Sphincterotomy
  Interventions:

  • Procedure: Pancreatic Sphincterotomy
  • Procedure: Pancreatic and Biliary Sphincterotomy
• Placebo Comparator: 2
  Sham procedure; during the ERCP no sphincterotomy procedure will be performed
  Intervention: Procedure: ERCP

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.