Sphincter of Oddi Dysfunction
Conditions
Keywords
Sphincter of Oddi Dysfunction, Pancreatitis, Sphincterotomy
Brief summary
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.
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.
Interventions
PROCEDUREERCP with sphincterotomy
cutting the biliary sphincter muscle (sphincterotomy)
PROCEDUREERCP without sphincterotomy
ERCP with sphincter manometry, but no sphincterotomy
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Success | 1 year | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With a Successful Primary Outcome, Out of Those With Abnormal Sphincter Manometry. | 1 year | 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. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from medical clinics in 6 gastroenterology referral centers in USA between August 6 2008 and March 23 2012.
Participants by arm
| Arm | Count |
|---|---|
| 1. ERCP With Sphincterotomy Endoscopic Retrograde CholangioPancreatography (ERCP) with sphincter manometry and biliary and/or pancreatic sphincterotomy and pancreatic stenting | 141 |
| 2. ERCP Without Sphincterotomy Endoscopic Retrograde CholangioPancreatography(ERCP) with sphincter manometry and pancreatic stenting, but without sphincterotomy | 73 |
| Total | 214 |
Baseline characteristics
| Characteristic | 1. ERCP With Sphincterotomy | 2. ERCP Without Sphincterotomy | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 141 Participants | 73 Participants | 214 Participants |
| Region of Enrollment United States | 141 participants | 73 participants | 214 participants |
| Sex: Female, Male Female | 128 Participants | 69 Participants | 197 Participants |
| Sex: Female, Male Male | 13 Participants | 4 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 141 | 0 / 73 |
| serious Total, serious adverse events | 16 / 141 | 12 / 73 |
Outcome results
Primary
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.
Time frame: 1 year
Population: The primary analysis was conducted with the intention-to-treat population defined as all randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1.ERCP With Sphincterotomy | Percentage of Participants With Success | 23 percentage of paricipants with success |
| 2. ERCP Without Sphincterotomy | Percentage of Participants With Success | 37 percentage of paricipants with success |
Comparison: The trial was designed to test for an overall absolute difference of at least 30% in the primary outcome ('success') in patients treated with sphincterotomy compared to those treated with sham. Using a 2:1 allocation, an assumed 10% non-adherence rate, and one interim analysis for efficacy using O'Brien and Fleming boundaries and futility using conditional power, the study required 214 patients to be randomized to ensure greater than 90% likelihood of identifying this difference.p-value: 0.0195% CI: [-28, -3.3]Regression, Logistic
Secondary
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.
Time frame: 1 year
Population: Participants with abnormal sphincter manometry
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1.ERCP With Sphincterotomy | Percentage of Patients With a Successful Primary Outcome, Out of Those With Abnormal Sphincter Manometry. | 24 percentage of participants with success |
| 2. ERCP Without Sphincterotomy | Percentage of Patients With a Successful Primary Outcome, Out of Those With Abnormal Sphincter Manometry. | 33 percentage of participants with success |
Comparison: Only patients with abnormal manometry were included in this subgroup analysis.95% CI: [-24.1, 5.9]