Lactated Ringers With or Without Rectal Indomethacin to Prevent Post-ERCP Pancreatitis

Phase 3

Completed

Conditions: Post-ERCP Acute Pancreatitis

Interventions: Drug: Normal Saline
Drug: Lactated Ringer's Solution
Drug: Indomethacin
Drug: Placebo

Registration Number: NCT02641561

Lead Sponsor: The Cooper Health System

Brief Summary: Post-ERCP pancreatitis is a well-known and sometimes life-threatening complication of ERCP. Both LR and rectal indomethacin have shown benefit in preventing post-ERCP pancreatitis. Despite this, no study to date has evaluated both of these measures for preventing post-ERCP pancreatitis. It is our hope to evaluate the combination of these two modalities for preventing post-ERCP pancreatitis compared with either modality alone.

Detailed Description: Endoscopic retrograde cholangiopancreatography (ERCP) is commonly used diagnostic and therapeutic intervention used in Gastroenterology. At Cooper University Hospital (CUH), we perform approximately 700 ERCPs per year. A known complication of ERCP is post-ERCP pancreatitis. The incidence of post-ERCP pancreatitis has been cited at anywhere from 2.6-3.5% of cases. Also, severe acute pancreatitis has been cited at rates of 0.32-0.4% and death 0.11%.

Recent literature has cited the use of several modalities useful in preventing post-ERCP pancreatitis. Among the modalities evaluated non-steroidal anti-inflammatory drugs (NSAIDS), specifically rectal indomethacin, have demonstrated benefit in preventing post-ERCP. In particular Elmunzer et al demonstrated a benefit in those with sphincter of oddi dysfunction (SOD) and those deemed "high risk" for post-ERCP pancreatitis. Other medication such at octreotoide and corticosteroid have shown mixed results.

Additionally, recent studies have demonstrated the use of lactated ringer's solution (LR) in lieu of normal saline (NS) in patient's with acute pancreatitis. Due to this thought process a recent study evaluated the use of LR in preventing post-ERCP pancreatitis. The results of this study showed that no patients who received aggressive LR hydration developed post-ERCP pancreatitis.

As rectal indomethacin and LR infusion appear to have the most definitive evidence for preventing post-ERCP pancreatitis, it is our hope to evaluate the combination of these two therapies for the prevention of post-ERCP pancreatitis.

This is a double blinded, randomized prospective cohort study involving 4 treatment groups undergoing ERCP.

All treatment arms shall receive consent, pre-procedural risk stratification, demographic data and pre-procedural liker pain scale. All subjects shall receive a study subject number and undergo randomization. All subjects also will receive post-procedural likert pain scale assessment, day 1 and 30 questioning. Treatment arms shall be separated into whether subjects are high risk or not defined in.

Time 0 (Visit 1):

Subjects undergo standard pre-procedural evaluation by nursing, anesthesia and consent for procedure/anesthesia.

The subject shall then be evaluated for study participation and subsequently consented if they desire to be part of the study. They may also undergo informed consent prior to the day of their procedure during their normal office visit. All subjects must have Liver function tests (LFTs), amylase and lipase levels drawn prior to their ERCP test. Subjects will be excluded from study participation if they have acute pancreatitis defined as;

The diagnosis of AP is most often established by the presence of 2 of the 3 following criteria:

(i) abdominal pain consistent with the disease (ii) serum amylase and / or lipase greater than three times the upper limit of normal, and / or (iii) characteristic findings from abdominal imaging

The day of their procedure, nursing shall then obtain intravenous peripheral access (standard for ERCP). Initial demographic data and risk factor data shall be obtained. Subjects shall then be randomized to one of the four study arms and given a study number randomly generated:

Pending which treatment arm the patient is enrolled into the subject shall then receive the above listed therapies and undergo their procedure.

Post-procedure the interventions performed during the ERCP shall be recorded and the patient will go through the standard recovery process. Post-procedure after recovery from anesthesia, the patients shall then be evaluated for the presence of pain after ERCP testing on the standard likert pain scale.

If the subject's pain has substantially increased from baseline, subjects shall then be admitted to the hospital and LFTs, a lipase and amylase level shall be drawn and abdominal imaging ordered if needed by the admitting physician (all the standard of care).

Time 1 Days (Visit 2 via phone):

Subjects shall be called 24 hours from ERCP to assess;

1. Presence/absence of pain

2. If pain, the severity

3. Performance of amylase and lipase

4. Whether admission, urgent care or emergency department visit did occur

Time 1-30 Days The investigator will await the subjects laboratory values and if \> 3 times the upper limit of normal contact the subject via phone.

Time 30 Days (Visit 3 via phone):

Subjects shall be contacted via phone 30 days from ERCP to assess;

1. Presence/absence of pain

2. If pain, the severity

3. Whether admission, urgent care or Emergency Department (ED) visit did occur to a healthcare facility

4. Study summary

To detect a difference of 0.24 vs 0.05 a minimum of 48 per group would be needed (using p=0.05).

Descriptive statistics will be used to summarize demographic variables such as age, gender, race, length of stay, as well diagnosis and disease characteristics such as reasons for ERCP, disease intervention, pain,and outcome variables. Data tables will be generated for those variables with means, standard deviation (SD), medians, interquartile range (IQR), and confidence interval (CI). The Chi-Square test will be used to determine the main effect of treatment on ERCP induced pancreatitis. Nonparametric tests will be used to analyze categorical data while normally distributed data will be analyzed using ANOVA to look for treatment effect on other variables of interest.

Binary and Multinomial Logistic Regression will be used to examine predictors of outcome within treatments and across treatments by building interactions into the model (e.g. reasons for ERCP, intervention type). Data analysis will be performed using Systat version 13 and SPSS version 22. A p\<0.05 will be considered statistically significant.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 192

Inclusion Criteria

1 Subjects who are undergoing endoscopic retrograde cholangiopancreatography (ERCP)

Age > 18 years
Non-pregnant
Non-prisoners
Subjects who can sign informed consent
Serum Creatinine < 1.2 milligrams/deciliter (mg/dL)
Subjects without renal failure (acute or chronic)
Subjects without congestive heart failure (ejection fraction < 40%)
Subjects without cirrhosis of the liver
Subjects without allergy to aspirin or non-steroidal anti-inflammatory drugs (NSAIDS)
Subjects not on non-steroidal anti-inflammatory drugs NSAIDS prior to enrollment

Exclusion Criteria

Subjects who are not undergoing ERCP
Age < 18 years
Pregnancy
Prisoners
Subjects lacking the capacity to consent for themselves
Serum Creatinine > 1.2 milligrams/deciliter (mg/dL)
Subjects with renal failure (acute and chronic)
Subjects with congestive heart failure (ejection fraction < 40%)
Subjects with cirrhosis of the liver
Subjects with allergy to aspirin or non-steroidal anti-inflammatory drugs (NSAIDS)
Subjects with gastrointestinal hemorrhage
Subjects on chronic non-steroidal anti-inflammatory drugs NSAIDS
Subjects with acute pancreatitis the day of their procedure (CITE 1-3)(APPENDIX 1)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
C (LR+Placebo)	Placebo	Lactated ringer's solution (1 Liter, intravenous prior to procedure) + Placebo (100mg suppository per rectum prior to procedure)
A (NS+Placebo)	Normal Saline	Normal Saline (intravenous during procedure) + Placebo (100mg suppository per rectum prior to procedure )
A (NS+Placebo)	Placebo	Normal Saline (intravenous during procedure) + Placebo (100mg suppository per rectum prior to procedure )
B (NS+IND)	Normal Saline	Normal Saline (intravenous during procedure) + Indomethacin (100mg suppository per rectum prior to procedure )
C (LR+Placebo)	Lactated Ringer's Solution	Lactated ringer's solution (1 Liter, intravenous prior to procedure) + Placebo (100mg suppository per rectum prior to procedure)
D (LR+IND)	Lactated Ringer's Solution	Lactated ringer's solution (1 Liter, intravenous prior to procedure) + Indomethacin (100mg suppository per rectum prior to procedure)
D (LR+IND)	Indomethacin	Lactated ringer's solution (1 Liter, intravenous prior to procedure) + Indomethacin (100mg suppository per rectum prior to procedure)
B (NS+IND)	Indomethacin	Normal Saline (intravenous during procedure) + Indomethacin (100mg suppository per rectum prior to procedure )

Primary Outcome Measures

Name	Time	Method
The Number of Participants With Acute Pancreatitis After ERCP as Assessed by Worsening Abdominal Pain Plus Either Elevated Amylase or Lipase 3 x Upper Limit of Normal	30 days after ERCP	amylase or lipase
The Number of Participants With Acute Pancreatitis After ERCP as Assessed by Worsening Abdominal Pain Plus Imaging Suggestive of Acute Pancreatitis	30 days after ERCP	Imaging may include Computer Tomography

Secondary Outcome Measures

Name	Time	Method
The Number of Participants With Acute Respiratory Distress Syndrome (ARDS) After ERCP as Assessed by ARDSnet Criterion (Below)	30 days after ERCP	bilateral opacities on chest imaging not explained by other lung pathology, respiratory failure not explained by heart failure or volume, and overload and a pulmonary arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio under 300, PaO2/FiO2 ratio is the partial pressure arterial oxygen and fraction of inspired oxygen
The Length of Stay (LOS) of Participants After ERCP if Medical Care is Sought as Assessed in Days	30 days after ERCP
The Number of Participants With Systemic Inflammatory Response Syndrome (SIRS) After ERCP as Assessed by the SIRS Criterion (Below)	30 days after ERCP	\> 10% immature neutrophils (band forms).
The Number of Participants With Sepsis After ERCP as Assessed by Infectious Source Defined by Positive Microbiology Culture	30 days after ERCP	positive blood culture
The Number of Participants With Multiple Organ Failure (MOF) After ERCP as Assessed by Elevated Creatinine Blood Test	30 days after ERCP	creatinine \> 1.5 milligrams/deciliter (mg/dL)
The Number of Participants With Multiple Organ Failure (MOF) After ERCP as Assessed by Elevated International Normalized Ratio (INR)	30 days after ERCP	INR \> 1.5
The Number of Participants With Pancreatic Pseudocyst After ERCP as Assessed by Abdominal Imaging Suggestive of Pseudocyst	30 days after ERCP	Imaging may include Computer Tomography
The Number of Participants With Pancreatic Abscess After ERCP as Assessed by Abdominal Imaging Suggestive of Pancreatic Abscess	30 days after ERCP	Imaging may include Computer Tomography
The Number of Participants With Perforation After ERCP as Assessed by Abdominal Imaging Suggestive of Perforation	30 days after ERCP	Imaging may include Computer Tomography
The Number of Participants Who Undergo Surgery After ERCP, as Assessed by Surgical Operative Report	30 days after ERCP
The Number of Participants With Mortality After ERCP as Assessed by Medical Record Reporting	30 days after ERCP
The Number of Participants With Post-procedural Medical Care (ED Visit, Urgent Care, Hospitalization) as Assessed by Medical Record and Patients Self-reporting	30 days after ERCP
The Number of Participants Who Were Readmitted After ERCP as Assessed by Medical Record and Patients Self-reporting	30 days after ERCP