Pancreatitis, Pancreas Divisum, Pancreatitis, Acute, Pancreatitis Idiopathic, Pancreas Inflamed
Conditions
Keywords
ERCP, Endoscopic retrograde cholangiopancreatography, pancreatitis
Brief summary
The purpose of this study is to determine if a procedure called Endoscopic Retrograde CholangioPancreatography (ERCP) with sphincterotomy reduces the risk of pancreatitis or the number of recurrent pancreatitis episodes in patients with pancreas divisum. ERCP with sphincterotomy is a procedure where doctors used a combination of x-rays and an endoscope (a long flexible lighted tube) to find the opening of the duct where fluid drains out of the pancreas. People who have been diagnosed with pancreas divisum, have had at least two episodes of pancreatitis, and are candidates for the ERCP with sphincterotomy procedure may be eligible to participate. Participants will be will be randomly assigned to either have the ERCP with sphincterotomy procedure, or to have a sham procedure. Participants will have follow up visits 30 days after the procedure, 6 months after the procedure, and continuing every 6 months until a maximum follow-up period of 48 months.
Detailed description
This is a sham-controlled, single blinded with a blinded outcome assessment, multi-center, randomized clinical trial of endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla endoscopic sphincterotomy (miES) for the treatment of recurrent acute pancreatitis (RAP) with pancreas divisum. ERCP with miES is often offered in clinical practice to patients with RAP, pancreas divisum, and no other clear risk factors for their acute pancreatitis episodes. The hypothesis is that obstruction at the level of the minor papilla is one cause of RAP in pancreas divisum; miES will relieve the obstruction, thereby reducing the risk of a recurrent attack(s) of acute pancreatitis. The trial requires a total sample size of approximately 234 subjects, and a planned enrollment period of approximately 3.5 years with total planned study duration of 5 years (minimum follow-up of 6 months, maximum follow-up of 48 months).
Interventions
PROCEDUREERCP with miES
Endoscopic retrograde cholangiopancreatography with minor papilla endoscopic sphincterotomy
PROCEDUREEUS
Endoscopic ultrasound
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Oregon Health and Science University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
In addition to the participant and the investigator assessing outcomes, study coordinators involved in collecting outcomes data will be masked to the treatment assignment.
Intervention model description
Subjects will be randomized 1:1 to either EUS+sham or EUS+ERCP with miES.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient must consent to be in the study and must have signed and dated an approved consent form. 2. \>18 years 3. Two or more episodes of acute pancreatitis, with each episode meeting two of the following three criteria: * abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating to the back) * serum lipase activity (or amylase activity) at least three times greater than the upper limit of normal * characteristic findings of acute pancreatitis on CECT, MRI or transabdominal ultrasonography 4. At least one episode of acute pancreatitis within 24 months of enrollment 5. Pancreas divisum confirmed by prior MRCP that is reviewed by an abdominal radiologist at the recruiting site. 6. By physician assessment, there is no certain explanation for recurrent acute pancreatitis. 7. Subjects must be able to fully understand and participate in all aspects of the study, including completion of questionnaires and telephone interviews, in the opinion of the clinical investigator
Exclusion criteria
1. Prior minor papilla therapy (endoscopic or surgical) 2. Calcific chronic pancreatitis, defined as parenchymal or ductal calcifications identified on computed tomography or magnetic resonance imaging scan that is reviewed by an expert radiologist at the recruiting site. 3. Main pancreatic duct stricture\* 4. Presence of a structural etiology for acute pancreatitis, such as anomalous pancreatobiliary union, periampullary mass, or pancreatic mass lesion on imaging\* 5. Presence of a local complication from acute pancreatitis which requires pancreatogram 6. Regular use of opioid medication for abdominal pain for the past three months 7. Medication as the etiology for acute pancreatitis by physician assessment 8. TWEAK score ≥ 4
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reduce the Risk of Subsequent Acute Pancreatitis Episodes by 33% | This is a time-to-event outcome that is assessed starting 30 days after treatment through a maximum follow-up of 48 months. | To test this aim, compare the incidence of acute pancreatitis \> 30 days after treatment allocation as the primary outcome measure, using the next attack of acute pancreatitis as a time-to-event outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Compare the Incidence Rate Ratio of Acute Pancreatitis Between Treatment Groups | Incidence rate will be assessed starting 30 days after treatment through a maximum follow-up of 48 months. | All randomized subjects will be followed longitudinally until study completion (minimum follow-up of six months, maximum follow-up of 48 months), even if acute pancreatitis occurs during follow-up. A secondary benefit of miES may be a reduction in acute pancreatitis frequency, defined as the incidence rate (episodes/time pre- and post-randomization). Since baseline incidence rate is a probable predictor of post-randomization incidence rate, the investigators will compare the incidence rate ratios between the two arms, keeping person-time equal between the pre/post periods. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| EUS + Sham Subjects randomized to EUS + sham will undergo a diagnostic endoscopic ultrasound (EUS) under sedation. The physician investigator will not make any attempts to achieve minor papilla cannulation, but photo document the minor papilla using a duodenoscope. Diluted dye will be injected into the duodenum. A small caliber prophylactic pancreatic duct stent will be deposited into the duodenal lumen. These maneuvers are performed to minimize the risk of unmasking.
EUS: Endoscopic ultrasound | 73 |
| EUS + ERCP With miES Subjects randomized to EUS + ERCP with miES will undergo the procedure at the same time as endoscopic ultrasound (EUS), under sedation. Indomethacin (100 mg) will be administered rectally at the onset of the ERCP procedure in patients with no known allergy to indomethacin. The techniques used to perform the endoscopic retrograde cholangiopancreatography (ERCP)with miES (minor papilla endoscopic sphincterotomy) will be left to the discretion of the study endoscopist. The extent of sphincterotomy will be per the discretion of the treating endoscopist. Unless methylene blue (or similar chromoendoscopy agent such as indigo carmine) has already been used to facilitate minor papilla cannulation, diluted dye will be injected into the duodenum.
ERCP with miES: Endoscopic retrograde cholangiopancreatography with minor papilla endoscopic sphincterotomy
EUS: Endoscopic ultrasound | 75 |
| Total | 148 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | EUS + ERCP With miES | Total | EUS + Sham |
|---|---|---|---|
| Age, Continuous | 56 Years | 54 Years | 52 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 7 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 71 Participants | 137 Participants | 66 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 11 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) White | 64 Participants | 129 Participants | 65 Participants |
| Sex: Female, Male Female | 49 Participants | 101 Participants | 52 Participants |
| Sex: Female, Male Male | 26 Participants | 47 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 73 | 2 / 75 |
| other Total, other adverse events | 8 / 73 | 15 / 75 |
| serious Total, serious adverse events | 48 / 73 | 48 / 75 |
Outcome results
Primary
Reduce the Risk of Subsequent Acute Pancreatitis Episodes by 33%
To test this aim, compare the incidence of acute pancreatitis \> 30 days after treatment allocation as the primary outcome measure, using the next attack of acute pancreatitis as a time-to-event outcome.
Time frame: This is a time-to-event outcome that is assessed starting 30 days after treatment through a maximum follow-up of 48 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EUS + Sham | Reduce the Risk of Subsequent Acute Pancreatitis Episodes by 33% | 32 Participants |
| EUS + ERCP with miES | Reduce the Risk of Subsequent Acute Pancreatitis Episodes by 33% | 26 Participants |
Secondary
To Compare the Incidence Rate Ratio of Acute Pancreatitis Between Treatment Groups
All randomized subjects will be followed longitudinally until study completion (minimum follow-up of six months, maximum follow-up of 48 months), even if acute pancreatitis occurs during follow-up. A secondary benefit of miES may be a reduction in acute pancreatitis frequency, defined as the incidence rate (episodes/time pre- and post-randomization). Since baseline incidence rate is a probable predictor of post-randomization incidence rate, the investigators will compare the incidence rate ratios between the two arms, keeping person-time equal between the pre/post periods.
Time frame: Incidence rate will be assessed starting 30 days after treatment through a maximum follow-up of 48 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EUS + Sham | To Compare the Incidence Rate Ratio of Acute Pancreatitis Between Treatment Groups | 0.304 Incidence rate ratio |
| EUS + ERCP with miES | To Compare the Incidence Rate Ratio of Acute Pancreatitis Between Treatment Groups | .246 Incidence rate ratio |