Ursodeoxycolic Acid for the Prevention of Relapsing Complications After Gallstone Acute Pancreatitis

Study Overview
=================
Brief Summary
-----------------
Acute pancreatitis is a common disease (3rd cause of hospital admission for digestive causes), which is associated with significant patient suffering, a 2-4% probability of death and considerable healthcare costs. Sixty percent of acute pancreatitis are due to the presence of stones in the gallbladder. The risk of suffering another acute biliary pancreatitis (ABP, that is to say, pancreatitis due to gallstones) or of other biliary complications in the following weeks or months is high (20% or greater) if measures are not taken to avoid it, being surgical removal of the gallbladder the most effective. Unfortunately, most Spanish centers have a surgical waiting list that makes gallbladder surgery unfeasible in a period of less than weeks or months, which is why readmission for biliary problems derived from the stones is a common problem. This, of course, causes danger and great stress and anger for patients affected by these complications on the waiting list, damaging their relationship with the health system and it is linked to increased cost. In addition, there is a very vulnerable group, those patients who due to age or serious diseases cannot undergo gallbladder surgery but have a high probability of suffering biliary problems due to the stones they have. Ursodeoxycholic acid (UDCA) is very safe drug which is used to dissolve gallstones, but its role in preventing biliary complications after ABP has not been studied adequately so it is not frequently used. Our objective is to investigate if UDCA is useful in this scenario, which would avoid suffering and adverse consequences for the patient and reduce the consumption of resources.

Official Title
-----------------
Ursodeoxycolic Acid for the Prevention of Relapsing Complications After Gallstone Acute Pancreatitis, a Double-blind Multicenter Randomized-controlled Trial. OSOPOLAR Trial

Conditions
-----------------
Acute Pancreatitis Due to Gallstones

Intervention / Treatment
-----------------
* Drug: Ursodeoxycholic Acid
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18 years old or older Hospital admission due to acute pancreatitis (definition: at least 2 of the following criteria: A) Typical pancreatitis pain, B) Amylase and/or lipase higher than 3 times the upper level of normality, C) Imaging compatible with acute pancreatitis Presence of gallstones according to any imaging technique Patient informed consent Exclusion Criteria: Cholecystectomy and/or endoscopic retrograde cholangio-pancreatography and / or endoscopic cholecystostomy prior to recruitment Recurrent acute pancreatitis (1 or more previous episodes of pancreatitis of any origin) Current waiting list for cholecystectomy for acute biliary pancreatitis at that center less than 30 days Randomization more than 3 days after hospital discharge for acute pancreatitis Ursodeoxycholic acid (UDCA) consumption in the last 5 years or previous UDCA failure to dissolve lithiasis Allergy, intolerance or presence of contraindications to UDCA (contraindicated in patients with active gastric or duodenal ulcer, liver or intestinal disorders that interfere with the enterohepatic circulation of bile salts and lactation) Presence of choledocholithiasis diagnosed by imaging tests prior to randomization Active alcoholism greater than or equal to 5 daily alcoholic drinks in men or 3 in women or high clinical suspicion of clinically significant alcoholism Recent history of significant therapeutic non-compliance or social problem that makes follow-up difficult Hypertriglyceridemia greater than 400 mg / dL during admission or history of poorly controlled severe hypertriglyceridemia Chronic pancreatitis (pancreatic calcifications and / or Wirsung duct 4 or more mm) Pancreatic cystic lesions not attributed to the pancreatitis itself Wirsung duct stenosis Primary hyperparathyroidism Pregnancy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: UDCA (Ursodeoxycholic Acid) group<br>Patients receiving Ursodeoxycholic Acid, capsules containing 300 mg, 10 mg/Kg per day: Patients 40 to 70 kg: 2 capsules/day >70 to 100 Kg: 3 capsules/day >100 kg: 4 capsules/day | Drug: Ursodeoxycholic Acid<br>* Ursodeoxycholic Acid will be administered to patients in the UDCA group as a prophylactic measure of future complications associated to gallstones<br>|
| Placebo Comparator: Placebo group<br>Capsules containing placebo, indistinguishable from active treatment. | Drug: Placebo<br>* Placebo: composition per 100g: colloidal silica 1.95g and cellulose microcrystalline 98.05g.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complication due to gallstones | Composite endpoint: incidence of any of the following: acute pancreatitis, acute cholangitis, acute cholecystitis, biliary colic (with or without choledocholithiasis) Definitions are provided in Secondary Outcome Measures | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse of acute pancreatitis | New episode of acute pancreatitis after recruitment Definition of acute pancreatitis (revised Atlanta classification): 2 or more of the following criteria: A) Typical pancreatitis pain, B) Amylase and/or lipase higher than 3 times the upper level of normality, C) Imaging compatible with acute pancreatitis | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 
| Incidence of acute cholangitis | Acute cholangitis after recruitment Acute cholangitis definition (Tokyo 2018 guidelines): A. Systemic inflammation: A-1. Fever and/or shaking chills; A-2. Laboratory data: evidence of inflammatory response B. Cholestasis: B-1. Jaundice; B-2. Laboratory data: abnormal liver function tests C. Imaging: C-1. Biliary dilatation; C-2. Evidence of the etiology on imaging (stricture, stone, stent etc.) Suspected diagnosis: one item in A + one item in either B or C Definite diagnosis: one item in A, one item in B and one item in C | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 
| Incidence of acute cholecystitis | Acute cholecystitis after recruitment Acute cholecystitis definition (Tokyo 2018 guidelines): A. Local signs of inflammation: (1) Murphy's sign, (2) RUQ mass/pain/tenderness B. Systemic signs of inflammation: (1) Fever, (2) elevated CRP, (3) elevated WBC count C. Imaging findings: Imaging findings characteristic of acute cholecystitis Suspected diagnosis: one item in A + one item in B Definite diagnosis: one item in A + one item in B + C | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 
| Incidence of biliary colic, with or without choledocholithiasis | Biliary colic after recruitment Biliary colic definition: typical biliary colic pain. Choledocholithiasis: presence of stones or biliary sludge in the common bile duct according to imaging or endoscopic retrograde cholangio-pancreatography | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 
| Effectiveness of ursodeoxycholic acid in treating gallstones | Decrease or elimination of gallstones according to ultrasonography | Abdominal ultrasonography will be performed at 6 and 12 months after recruitment unless cholecystectomy is performed | 
| EORTC-QLQ C30 questionnaire | EORTC-QLQ C30 questionnaire as a measure of Quality of Life | Measurement at 1, 3, 6, 9 and 12 months after recruitment | 
| Hospital stay during follow-up | Number of days admitted due to symptomatic gallstone disease | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 
| Intensive care unit stay during follow-up | Number of days admitted in the intensive care unit due to symptomatic gallstone disease | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 
| Adverse events | Adverse events due to ursodeoxycolic acid or placebo | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 
| Number of visits to emergency room or hospital admissions due to symptomatic gallstone disease | Number of visits to emergency room or hospital admissions due to symptomatic gallstone disease | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 
| Need for endoscopic retrograde cholangio-pancreatography (ERCP) during follow-up | Need for ERCP due to choledocholithiasis or acute cholangitis | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 
| Need for gallbladder endoscopic or percutaneous drainage during follow-up | Need for gallbladder endoscopic or percutaneous drainage due to acute cholecystitis or cholangitis | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 
| Need for drainage of collections and abscesses | Need for drainage of collections and abscesses (liver abscess, symtomatic pancreatic or peripancreatic collections not related to the index acute pancreatitis) | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 
| Incidence of organ failure during follow-up | Organ failure definition (revised Atlanta classification): PaO2/FIO2<300, Creatinine >=1.9 mg/dl and/or systolic blood pressure <90mmHg despite fluid resuscitation | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 
| Mortality | Death during follow-up | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 
| Need for urgent cholecystectomy | Need for urgent cholecystectomy for acute gallbladder complication, mainly acute cholecystitis | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 
| Need for surgical necrosectomy | Need for surgical necrosectomy, mainly after infection of pancreatic necrosis (not related to the index acute pancreatitis) | From recruitment to cholecystectomy or up to 1 year after recruitment if cholecystectomy is not performed | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute pancreatitis, Gallstones, Ursodeoxycholic Acid, Randomized Controlled Trial