Rectal Indomethacin in the Prevention of Post-ERCP Pancreatitis

• Sponsor: Indiana University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01912716
• Collaborator: American College of Gastroenterology (Other), University of Michigan (Other), University of Texas (Other), Aurora Health Care (Other), Medical University of South Carolina (Other), Beth Israel Deaconess Medical Center (Other)
• Enrollment: 1,037
• Locations: 6
• Arms: 2
• Duration (Months): 63
• Patients Per Site: 172.8
• Patients Per Site Per Month: 2.7

Study Details

Study Description

Brief Summary

It is now established that indomethacin, a non-steroidal anti-inflammatory drug, at a dose of 100 mg, is effective in reducing the frequency and severity of pancreatitis (inflammation of the pancreas) after endoscopic retrograde cholangiopancreatography (ERCP) in high risk patients. However, the optimal dose required is not known. The purpose of this study is to determine whether a dose of 200 mg, administered as rectal suppositories, is more effective than the standard dose of 100 mg. An ERCP procedure is a scope procedure where a lighted tube with a camera is passed down the patient's throat and allows for evaluation of the bile duct and/or pancreatic duct. The most common side effect of this procedure is post-ERCP pancreatitis, or swelling of the pancreas. Some patients are at higher risk for this complication than others. Our hypothesis is to compare the efficacy of these two dose regimens (100 mg vs 200 mg) of prophylactic rectally-administered indomethacin on the frequency and severity of post-ERCP pancreatitis in high-risk patients.

Condition or Disease	Intervention/Treatment	Phase
Post-ERCP Pancreatitis	Drug: high dose indomethacin; Drug: standard dose indomethacin	Phase 2/Phase 3

Detailed Description

After obtaining informed consent, subjects will undergo ERCP per clinical protocol. All procedure-related clinical decisions and interventions will be dictated by the performing physician as he or she sees fit. At the end of the procedure, it will be determined by the endoscopist and research coordinator whether the patient meets inclusion criteria. If inclusion criteria are met, subjects will be randomized by concealed allocation to receive either 100mg or 150mg indomethacin, in the form of two or three 50mg rectal suppositories. Those patients who are randomized to receive the 100mg dose will receive an additional glycerin suppository. Four hours later, those patients who were randomized to the high-dose group will then receive an additional 50mg suppository while in the recovery area. At this same time point, subjects who were randomized to the standard-dose group, will receive a glycerin suppository in the recovery area. All participating patients will receive a total of 4 suppositories.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1037 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Rectal Indomethacin in the Prevention of Post-ERCP Pancreatitis in High Risk Patients: Searching for the Optimal Dose. A Prospective, Randomized Trial
• Study Start Date: Jul 1, 2013
• Actual Primary Completion Date: Apr 1, 2018
• Actual Study Completion Date: Oct 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: high-dose indomethacin 200mg rectal indomethacin	Drug: high dose indomethacin; patients randomized to this intervention receive 200mg indomethacin; Other Names: Indocin
Active Comparator: standard dose indomethacin 100mg rectal indomethacin	Drug: standard dose indomethacin; patients randomized to this intervention receive 100mg indomethacin; Other Names: Indocin

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Developed Post-ERCP Pancreatitis [5 days]

   Assessment of whether patients developed post-ERCP pancreatitis, defined as a new onset of pain (or worsening of existing pain) in the upper abdomen, an elevation in pancreatic enzymes of at least three times the upper limit of the normal range 24 hours after the procedure, and hospitalization for at least two nights.

Secondary Outcome Measures

1. Number of Participants With Moderate or Severe Post-ERCP Pancreatitis [30 days]

   Assessment of whether patients developed either moderate or severe post-ERCP pancreatitis, defined according to established consensus criteria (Cotton et al., Gastrointestinal Endoscopy 1991;37:383-93). Severity of post-ERCP pancreatitis is partly defined according to length of stay. Moderate pancreatitis is defined as a 4-10 day hospitalization. Severe post-ERCP pancreatitis is defined as a hospitalization of greater than 10 days post-ERCP, or development of a complication (eg. pseudocyst or necrosis), or need for intervention (drainage or surgery).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Included patients are those undergoing Endoscopic Retrograde Cholangiopancreatography (ERCP) and have:

one of the following:

1. Clinical suspicion of sphincter of Oddi dysfunction (SOD; type I or II)

2. History of post-ERCP pancreatitis (at least one episode)

3. Pancreatic sphincterotomy

4. Pre-cut (access) sphincterotomy

5. greater than 8 cannulation attempts of any sphincter

6. Pneumatic dilation of intact biliary sphincter

7. Ampullectomy 8.) Assessment for post-sphincterotomy stenosis

OR at least 2 of the following:

1. Age less than 50 years old and female gender

2. History of recurrent pancreatitis (at least 2 episodes)

3. greater than or equal to to 3 pancreatic injections, with at least 1 injection to tail

4. Pancreatic acinarization (excluding ventral pancreas of pancreas divisum)

5. Pancreatic brush cytology -

Exclusion Criteria:

1. Unwillingness or inability to consent for the study

2. Age less than 18 years

3. Intrauterine pregnancy

4. Breastfeeding mother

5. Standard contraindications to ERCP

6. Allergy/hypersensitivity to aspirin or Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

7. Received NSAIDs in prior 7 days (aspirin 325mg or less ok)

8. Renal failure (serum creatinine greater than 1.4)

9. Active or recurrent (within 4 weeks) gastrointestinal hemorrhage

10. Acute pancreatitis (lipase peak) within 72 hours

11. Known chronic calcific pancreatitis

12. Pancreatic head mass

13. Procedure performed on major papilla/ventral pancreatic duct in patient with pancreas divisum (dorsal duct not attempted on injected)

14. ERCP for biliary stent removal or exchange without anticipated pancreatogram

15. Subject with prior biliary sphincterotomy now scheduled for repeat biliary therapy without anticipated pancreatogram

16. Anticipated inability to follow protocol

17. Known active cardiovascular or cerebrovascular disease -

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Indiana University Health	Indianapolis	Indiana	United States	46202
2	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
3	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
4	Medical University of South Carolina	Charleston	South Carolina	United States	29425
5	Methodist Dallas Medical Center	Dallas	Texas	United States	75203
6	Aurora St. Lukes' Medical Center	Milwaukee	Wisconsin	United States	53220

Sponsors and Collaborators

• Indiana University
• American College of Gastroenterology
• University of Michigan
• University of Texas
• Aurora Health Care
• Medical University of South Carolina
• Beth Israel Deaconess Medical Center

Investigators

• Principal Investigator: Evan L Fogel, MD, MSc, Indiana University Health

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 13, 2017

More Information

Publications

None provided.

• Responsible Party: Evan Fogel, Professor of Medicine, Indiana University
• ClinicalTrials.gov Identifier: NCT01912716
• Other Study ID Numbers: PEP INDO 2013; ACG-CR-002-2013
• First Posted: Jul 31, 2013
• Last Update Posted: Jul 5, 2019
• Last Verified: Jun 1, 2019

• Keywords provided by Evan Fogel, Professor of Medicine, Indiana University: pancreatitis; ERCP
• Additional relevant MeSH terms: Pancreatitis; Indomethacin

Study Results

Participant Flow

Recruitment Details	Patients were recruited between July 2013 - March 2018, either from the ERCP (Endoscopic Retrograde Cholangiopancreatography) outpatient clinic or Peri-Operative Care Unit immediately prior to ERCP.

Arm/Group Title	High-dose Indomethacin	Standard Dose Indomethacin
Arm/Group Description	200mg rectal indomethacin high dose indomethacin	100mg rectal indomethacin standard dose
Period Title: Overall Study
STARTED	522	515
Receipt of 2nd Dose	511	503
5-day Follow-up	522	515
3-day Follow-up	521	513
COMPLETED	522	515
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Standard Dose Group	High Dose Group	Total
Arm/Group Description	Participants randomized to this group receive 100 mg indomethacin	Participants randomized to this group receive 200 mg indomethacin	Total of all reporting groups
Overall Participants	515	522	1037
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.3 (15.2)	50.4 (15)	49.9 (15.1)
Sex: Female, Male (Count of Participants)
Female	392 76.1%	421 80.7%	813 78.4%
Male	123 23.9%	101 19.3%	224 21.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	20 3.9%	15 2.9%	35 3.4%
Not Hispanic or Latino	493 95.7%	507 97.1%	1000 96.4%
Unknown or Not Reported	2 0.4%	0 0%	2 0.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 0.4%	3 0.6%	5 0.5%
Asian	1 0.2%	1 0.2%	2 0.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	16 3.1%	12 2.3%	28 2.7%
White	485 94.2%	501 96%	986 95.1%
More than one race	2 0.4%	1 0.2%	3 0.3%
Unknown or Not Reported	9 1.7%	4 0.8%	13 1.3%
BMI (kg/m^2) [Geometric Mean (Standard Deviation) ]
Geometric Mean (Standard Deviation) [kg/m^2]	28.6 (7.0)	29.2 (7.6)	28.9 (7.3)
Obese (Count of Participants)
Count of Participants [Participants]	193 37.5%	198 37.9%	391 37.7%
Clinical Suspicion of SOD (sphincter of Oddi dysfunction) (Count of Participants)
Count of Participants [Participants]	319 61.9%	331 63.4%	650 62.7%
History of post-ERCP pancreatitis (Count of Participants)
Count of Participants [Participants]	77 15%	100 19.2%	177 17.1%
History of recurrent pancreatitis (Count of Participants)
Count of Participants [Participants]	202 39.2%	210 40.2%	412 39.7%
Difficult Cannulation (Count of Participants)
Count of Participants [Participants]	148 28.7%	146 28%	294 28.4%
Precut sphincterotomy (Count of Participants)
Count of Participants [Participants]	71 13.8%	46 8.8%	117 11.3%
Double-wire cannulation technique (Count of Participants)
Count of Participants [Participants]	18 3.5%	18 3.4%	36 3.5%
Pancreatography (patients) (Count of Participants)
Count of Participants [Participants]	446 86.6%	433 83%	879 84.8%
Number of pancreatic duct injections (injections) [Geometric Mean (Standard Deviation) ]
Geometric Mean (Standard Deviation) [injections]	2.12 (1.63)	1.96 (1.66)	2.04 (1.64)
Therapeutic pancreatic sphincterotomy (Count of Participants)
Count of Participants [Participants]	245 47.6%	231 44.3%	476 45.9%
Placement of pancreatic stent (Count of Participants)
Count of Participants [Participants]	400 77.7%	393 75.3%	793 76.5%
Ampullectomy (Count of Participants)
Count of Participants [Participants]	30 5.8%	32 6.1%	62 6%
Biliary sphincterotomy (Count of Participants)
Count of Participants [Participants]	302 58.6%	290 55.6%	592 57.1%
Trainee involvement (Count of Participants)
Count of Participants [Participants]	84 16.3%	68 13%	152 14.7%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Developed Post-ERCP Pancreatitis
Description	Assessment of whether patients developed post-ERCP pancreatitis, defined as a new onset of pain (or worsening of existing pain) in the upper abdomen, an elevation in pancreatic enzymes of at least three times the upper limit of the normal range 24 hours after the procedure, and hospitalization for at least two nights.
Time Frame	5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard 100mg Dose	High Dose 200 mg
Arm/Group Description	patients receiving 100mg indomethacin	patients receiving 200mg indomethacin
Measure Participants	515	522
Count of Participants [Participants]	76 14.8%	65 12.5%

2. Secondary Outcome

Title	Number of Participants With Moderate or Severe Post-ERCP Pancreatitis
Description	Assessment of whether patients developed either moderate or severe post-ERCP pancreatitis, defined according to established consensus criteria (Cotton et al., Gastrointestinal Endoscopy 1991;37:383-93). Severity of post-ERCP pancreatitis is partly defined according to length of stay. Moderate pancreatitis is defined as a 4-10 day hospitalization. Severe post-ERCP pancreatitis is defined as a hospitalization of greater than 10 days post-ERCP, or development of a complication (eg. pseudocyst or necrosis), or need for intervention (drainage or surgery).
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

development of moderate or severe post-ERCP pancreatitis

Arm/Group Title	Standard Dose 100 mg	High Dose 200mg
Arm/Group Description	patients receiving 100mg indomethacin	patients receiving 200mg indomethacin
Measure Participants	515	522
Count of Participants [Participants]	28 5.4%	28 5.4%

Adverse Events

Time Frame	Adverse event data were collected throughout the length of the study, i.e. 5 years. Patients were recruited from July 2013 until March 2018. Following recruitment of the last patient (i.e. #1037), follow-up for an additional 30-day period was undertaken to capture severity of pancreatitis (should it occur) and delayed adverse events.
Adverse Event Reporting Description	In this study, there was no difference in definition of adverse events or serious adverse events, as other [not including serious] adverse events were not monitored/assessed. All patients provided contact information (home phone, cell phone, personal e-mail address) at study entry, and patients were then contacted at 5 and 30 days to assess for these adverse events, as noted in the study protocol.
Arm/Group Title	Standard-dose Indomethacin		High-dose Indomethacin
Arm/Group Description	100mg rectal indomethacin standard dose indomethacin		200mg rectal indomethacin high-dose dose
All Cause Mortality
	Standard-dose Indomethacin		High-dose Indomethacin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/515 (0%)		0/522 (0%)
Serious Adverse Events
	Standard-dose Indomethacin		High-dose Indomethacin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	83/515 (16.1%)		77/522 (14.8%)
Cardiac disorders
myocardial infarction	1/515 (0.2%)	1	0/522 (0%)	0
Gastrointestinal disorders
pancreatitis	76/515 (14.8%)	76	65/522 (12.5%)	65
bleeding	6/515 (1.2%)	6	8/522 (1.5%)	8
Immune system disorders
allergy	0/515 (0%)	0	0/522 (0%)	0
Nervous system disorders
transient ischaemic attack	0/515 (0%)	0	1/522 (0.2%)	1
Renal and urinary disorders
renal failure	0/515 (0%)	0	3/522 (0.6%)	3
Other (Not Including Serious) Adverse Events
	Standard-dose Indomethacin		High-dose Indomethacin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

This study took place at 6 tertiary medical centers in the United States. However, approximately 3/4 of patients were enrolled from a single site.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.