Post-ERCP Pancreatitis
Conditions
Brief summary
Background: Pancreatitis is the most frequent complication of endoscopic retrograde cholangiopancreatography (ERCP), accounting for substantial morbidity, occasional mortality, and increased health care expenditures. Until recently, the only effective method of preventing post-ERCP pancreatitis (PEP) had been prophylactic pancreatic stent placement (PSP), an intervention that is costly, time consuming, technically challenging, and potentially dangerous. The investigators recently reported the results of a large randomized controlled trial demonstrating that rectal indomethacin, a non-steroidal anti-inflammatory drug, reduced the risk of pancreatitis after ERCP in high-risk patients, most of whom (\>80%) had received a pancreatic stent. Secondary analysis of this RCT suggested that subjects who received indomethacin alone were less likely to develop PEP than those who received a pancreatic stent alone or the combination of indomethacin and stent, even after adjusting for underlying differences in subject risk. If indomethacin were to obviate the need for PSP, major clinical and cost benefits in ERCP practice could be realized. Objective: To assess whether rectal indomethacin alone is non-inferior to the combination of rectal indomethacin and prophylactic pancreatic stent placement for preventing post-ERCP pancreatitis in high-risk cases. Methods: Comparative effectiveness multi-center non-inferiority trial of rectal indomethacin alone vs. the combination of rectal indomethacin and prophylactic pancreatic stent placement for the prevention of post-ERCP pancreatitis in high-risk patients. One thousand four hundred and thirty subjects at elevated risk for PEP who would normally receive a pancreatic stent for prophylaxis will be randomized to indomethacin alone or the combination of indomethacin and PSP. The proportion of patients developing PEP and moderate-severe PEP will be compared. In addition, the investigators will establish a quality-assured central repository of biological specimens obtained from study participants, permitting future translational research elucidating the molecular and genetic mechanisms of PEP, as well as the mechanisms by which non-steroidal anti-inflammatory drugs prevent this complication.
Detailed description
The purpose of the SVI study is to determine whether or not rectal indomethacin has no important loss of efficacy as compared to the combination of rectal indomethacin and prophylactic pancreatic stent placement in patients undergoing high-risk ERCP who require pancreatic stent placement (PSP) for the sole purpose of pancreatitis prevention. The primary efficacy endpoint is defined as post-ERCP pancreatitis defined per consensus (Altanta) criteria. Another way of stating the trial's purpose is that the proportion of subjects with post-ERCP pancreatitis on rectal indomethacin alone is not more than that of the combination of rectal indomethacin and prophylactic PSP by more than a pre-specified absolute amount (i.e., the non-inferiority margin). This is a blinded, two-armed non-inferiority trial where eligible patients will be randomized to either the combination treatment or indomethacin alone. Participants will be randomized during the ERCP procedure after eligibility is confirmed, and receive indomethacin at the time of randomization. The primary efficacy endpoint of post-ERCP pancreatitis within 2 days from randomization will be assessed by an independent adjudication panel. The participant follow-up period is 30 days from randomization.
Interventions
OTHERIndomethacin 100 mg rectally immediately after ERCP, NO prophylactic pancreatic stent placement
OTHERIndomethacin 100 mg rectally immediately after ERCP AND prophylactic pancreatic stent placement
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
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Any patient undergoing ERCP in whom pancreatic stent placement is planned for post-ERCP pancreatitis prevention, is ≥ 18 years old, who provides informed consent, AND: Has one of the following: 1. Clinical suspicion of or known sphincter of Oddi dysfunction 2. History of post-ERCP pancreatitis (at least one prior episode of pancreatitis after ERCP) 3. Pancreatic sphincterotomy 4. Pre-cut (access) sphincterotomy (freehand pre-cut and septotomy) 5. Difficult cannulation: cannulation duration ≥ 6 minutes (starting at time of initial papillary engagement with at least 25% of the time in contact with the papilla) AND/OR ≥ 6 cannulation attempts (defined as sustained contact with papilla lasting at least 1 second). 6. Short-duration (≤ 1 min) balloon dilation of an intact biliary sphincter. Or has at least 2 of the following: 7. Age \< 50 years old & female gender 8. History of recurrent pancreatitis (at least 2 episodes) 9. ≥3 pancreatic injections 10. Pancreatic acinarization 11. Pancreatic brush cytology
Exclusion criteria
1. Ampullectomy 2. Cases in which a pancreatic stent must be placed for therapeutic intent 3. Unwillingness or inability to consent for the study 4. Pregnancy 5. Breast feeding mother 6. Standard contraindications to ERCP 7. Allergy to Aspirin or NSAIDs 8. Known renal failure (Cr \> 1.4 mg/dl) 9. Ongoing or recent (within 2 weeks) hospitalization for gastrointestinal hemorrhage 10. Ongoing or recent (within 1 week) hospitalization for acute pancreatitis 11. Known chronic calcific pancreatitis 12. Pancreatic head malignancy 13. Procedure performed on major papilla/ventral pancreatic duct in patient with pancreas divisum (no manipulation of minor papilla) 14. ERCP for biliary stent removal or exchange without anticipated pancreatogram 15. Subjects with prior biliary sphincterotomy now scheduled for repeat biliary therapy without anticipated pancreatogram 16. Anticipated inability to follow protocol 17. Absence of rectum
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Subjects in Each Study Group With Post-ERCP Pancreatitis | Within 48 hours after ERCP | Post-ERCP pancreatitis (PEP) was based on a widely validated consensus definition that was applied as a diagnostic framework. In this consensus definition, PEP is diagnosed if there was new onset (or increase) of pain in the upper abdomen, elevation in pancreatic enzymes of at least three times the upper limit of normal 24 h after the procedure, and hospitalization for at least two nights. The outcome was independently adjudicated by 3 ERCP experts at non-enrolling centers based on review of the medical records for study participants who were hospitalized with any adverse event within 2 days of the ERCP. Medical records were redacted of all information that could potentially reveal study group assignment, including radiology reports. The consensus definition was applied as a diagnostic framework so that adjudicators could use their best judgment in cases that did not strictly satisfy the criteria. PEP was declared if there was agreement between at least two of the three adjudicators. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Subjects in Each Study Group With Moderate-severe Post-ERCP Pancreatitis | Within one month of ERCP | Moderate or severe post-ERCP pancreatitis was based on the consensus definition as a diagnostic framework. For the severity assessment, radiographic information was made available to the adjudicators. The severity was defined as mild post-ERCP pancreatitis resulting in a hospitalization of ≤3 days, moderate post-ERCP pancreatitis resulting in a hospitalization of 4-10 days, and severe post-ERCP pancreatitis resulting in a hospitalization of \> 10 days, or leading to the development of pancreatic necrosis or pseudocyst, or requiring percutaneous or surgical intervention. The outcome was declared if there was agreement between at least two of the three adjudicators. |
Countries
Canada, United States
Participant flow
Recruitment details
Patients were recruited from 20 referral centers in the USA and Canada between September 2015 and January 2023.
Pre-assignment details
Of 7243 patients assessed for eligibility, 1950 met eligibility criteria and were randomly assigned to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Indomethacin Alone Indomethacin 100 mg rectally immediately after ERCP, NO prophylactic pancreatic stent placement | 975 |
| Indomethacin+Pancreatic Stent Indomethacin 100 mg rectally immediately after ERCP AND prophylactic pancreatic stent placement | 975 |
| Total | 1,950 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Indomethacin Alone | Indomethacin+Pancreatic Stent |
|---|---|---|---|
| Age, Continuous | 55.7 years STANDARD_DEVIATION 16.4 | 55.6 years STANDARD_DEVIATION 16.4 | 55.8 years STANDARD_DEVIATION 16.3 |
| Antibiotic use in past 3 months | 729 Participants | 363 Participants | 366 Participants |
| Biliary sphincterotomy | 1733 Participants | 864 Participants | 869 Participants |
| BMI | 29.1 kg/m^2 STANDARD_DEVIATION 7 | 28.6 kg/m^2 STANDARD_DEVIATION 6.8 | 29.6 kg/m^2 STANDARD_DEVIATION 7.2 |
| Clinical suspicion or known sphincter of Oddi dysfunction | 514 Participants | 262 Participants | 252 Participants |
| Difficult cannulation | 1618 Participants | 795 Participants | 823 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 200 Participants | 101 Participants | 99 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1737 Participants | 866 Participants | 871 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 13 Participants | 8 Participants | 5 Participants |
| History of post-ERCP pancreatitis | 60 Participants | 36 Participants | 24 Participants |
| History of recurrent pancreatitis | 254 Participants | 128 Participants | 126 Participants |
| Number of pancreatic injections | 1 injections | 0 injections | 1 injections |
| Pancreatic acinarisation | 14 Participants | 6 Participants | 8 Participants |
| Pancreatic sphincterotomy | 124 Participants | 58 Participants | 66 Participants |
| Precut (access) sphincterotomy | 212 Participants | 112 Participants | 100 Participants |
| Prophylactic pancreatic stent calibre in those who received a stent 3 French | 18 Participants | 0 Participants | 18 Participants |
| Prophylactic pancreatic stent calibre in those who received a stent 4 French | 169 Participants | 4 Participants | 165 Participants |
| Prophylactic pancreatic stent calibre in those who received a stent >5 French | 18 Participants | 0 Participants | 18 Participants |
| Prophylactic pancreatic stent calibre in those who received a stent 5 French | 595 Participants | 9 Participants | 586 Participants |
| Prophylactic pancreatic stent calibre in those who received a stent Missing | 3 Participants | 3 Participants | 0 Participants |
| Prophylactic pancreatic stent length in those who received a stent 2-5cm | 462 Participants | 7 Participants | 455 Participants |
| Prophylactic pancreatic stent length in those who received a stent 6-8cm | 98 Participants | 3 Participants | 95 Participants |
| Prophylactic pancreatic stent length in those who received a stent >8cm | 240 Participants | 3 Participants | 237 Participants |
| Prophylactic pancreatic stent length in those who received a stent Missing | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 7 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 36 Participants | 17 Participants | 19 Participants |
| Race (NIH/OMB) Black or African American | 217 Participants | 115 Participants | 102 Participants |
| Race (NIH/OMB) More than one race | 10 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 43 Participants | 26 Participants | 17 Participants |
| Race (NIH/OMB) White | 1634 Participants | 809 Participants | 825 Participants |
| Sex: Female, Male Female | 1195 Participants | 599 Participants | 596 Participants |
| Sex: Female, Male Male | 755 Participants | 376 Participants | 379 Participants |
| Total intravenous fluid received during periprocedural period, mL | 1824 mL STANDARD_DEVIATION 937 | 1796 mL STANDARD_DEVIATION 935 | 1852 mL STANDARD_DEVIATION 938 |
| Total intravenous lactated Ringer's fluid received during periprocedural period, mL | 1581 mL STANDARD_DEVIATION 1069 | 1554 mL STANDARD_DEVIATION 1052 | 1606 mL STANDARD_DEVIATION 1085 |
| Trainee involvement | 1101 Participants | 555 Participants | 546 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 24 / 975 | 26 / 975 |
| other Total, other adverse events | 233 / 975 | 228 / 975 |
| serious Total, serious adverse events | 355 / 975 | 352 / 975 |
Outcome results
Primary
The Proportion of Subjects in Each Study Group With Post-ERCP Pancreatitis
Post-ERCP pancreatitis (PEP) was based on a widely validated consensus definition that was applied as a diagnostic framework. In this consensus definition, PEP is diagnosed if there was new onset (or increase) of pain in the upper abdomen, elevation in pancreatic enzymes of at least three times the upper limit of normal 24 h after the procedure, and hospitalization for at least two nights. The outcome was independently adjudicated by 3 ERCP experts at non-enrolling centers based on review of the medical records for study participants who were hospitalized with any adverse event within 2 days of the ERCP. Medical records were redacted of all information that could potentially reveal study group assignment, including radiology reports. The consensus definition was applied as a diagnostic framework so that adjudicators could use their best judgment in cases that did not strictly satisfy the criteria. PEP was declared if there was agreement between at least two of the three adjudicators.
Time frame: Within 48 hours after ERCP
Population: Intention-To-Treat and Per Protocol populations
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Indomethacin Alone | The Proportion of Subjects in Each Study Group With Post-ERCP Pancreatitis | Intention-To-Treat Population | 145 Participants |
| Indomethacin Alone | The Proportion of Subjects in Each Study Group With Post-ERCP Pancreatitis | Per Protocol Population | 137 Participants |
| Indomethacin+Pancreatic Stent | The Proportion of Subjects in Each Study Group With Post-ERCP Pancreatitis | Per Protocol Population | 90 Participants |
| Indomethacin+Pancreatic Stent | The Proportion of Subjects in Each Study Group With Post-ERCP Pancreatitis | Intention-To-Treat Population | 110 Participants |
95% CI: [0.006, 0.066]
95% CI: [-0.003, 0.06]
Secondary
The Proportion of Subjects in Each Study Group With Moderate-severe Post-ERCP Pancreatitis
Moderate or severe post-ERCP pancreatitis was based on the consensus definition as a diagnostic framework. For the severity assessment, radiographic information was made available to the adjudicators. The severity was defined as mild post-ERCP pancreatitis resulting in a hospitalization of ≤3 days, moderate post-ERCP pancreatitis resulting in a hospitalization of 4-10 days, and severe post-ERCP pancreatitis resulting in a hospitalization of \> 10 days, or leading to the development of pancreatic necrosis or pseudocyst, or requiring percutaneous or surgical intervention. The outcome was declared if there was agreement between at least two of the three adjudicators.
Time frame: Within one month of ERCP
Population: Intention-to-treat and per protocol. Outcome data missing for two participants (one in each treatment arm) and excluded from percentage denominator.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Indomethacin Alone | The Proportion of Subjects in Each Study Group With Moderate-severe Post-ERCP Pancreatitis | Intention-to-treat population | 78 Participants |
| Indomethacin Alone | The Proportion of Subjects in Each Study Group With Moderate-severe Post-ERCP Pancreatitis | Per protocol population | 74 Participants |
| Indomethacin+Pancreatic Stent | The Proportion of Subjects in Each Study Group With Moderate-severe Post-ERCP Pancreatitis | Intention-to-treat population | 58 Participants |
| Indomethacin+Pancreatic Stent | The Proportion of Subjects in Each Study Group With Moderate-severe Post-ERCP Pancreatitis | Per protocol population | 45 Participants |
95% CI: [-0.002, 0.043]
95% CI: [-0.004, 0.044]