Simvastatin in the Prevention of Recurrent Pancreatitis

Study Overview
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Brief Summary
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Recurrent acute pancreatitis and recurrent relapses of inflammation in chronic pancreatitis are an important problem. In some cases, prevention of these acute flares of inflammation is not possible. Population-based studies and meta-analysis of randomized controlled trials suggest that statins may decrease the incidence of acute pancreatitis. SIMBA aims to investigate the effect of simvastatin on the incidence of new episodes of pancreatitis in recurrent acute pancreatitis and chronic pancreatitis. This is a non-profit, researcher-driven placebo-controlled multicenter (27 Spanish centers) randomized controlled trial

Detailed Description
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Acute pancreatitis (AP) is the 3rd cause of hospital admission due to gastrointestinal disease. Approximately 20% of the patients will relapse after a first episode of AP. The low frequency of relapse in biliary AP is due to the high effectiveness of cholecystectomy but a first episode of AP due to alcoholic or other etiologies is associated with relapse in one every four patients. Currently, besides counselling for alcohol and tobacco abstinence, there is no specific medical treatment that changes the natural history of recurrent AP. Recurrent AP is an intermediary stage in the pathogenesis of chronic pancreatitis (CP) and a subset of recurrent AP patients during their natural course transition to CP (one every three patients). Forty-five percent of patients with CP experience intermittent flares of pain. Simvastatin has been associated to a decrease in the incidence of AP in a population-based study (Wu et al, Gut. 2015) and in a meta-analysis of randomized controlled trials (Preiss et al, JAMA 2012). The main aim of SIMBA (SIMvastatin in the prevention of recurrent pancreatitis, a triple Blind rAndomized controlled multicenter trial) is to compare the recurrence rate of pancreatitis in patients with established recurrent pancreatitis (acute pancreatitis and acute flares in chronic pancreatitis) consuming simvastatin versus placebo. The secondary aims are 1) to compare in patients with recurrent AP at the end of follow-up period the progression to chronic pancreatitis on imaging (calcifications and/or dilated ductal system), as well as endocrine and exocrine pancreatic function; 2) to compare the severity of recurrent pancreatitis between both treatment arms. Design: SIMBA is a triple-blind randomized placebo-controlled, parallel-group, superiority multicenter (27 Spanish centers) trial. This final protocol (version 4) was finished on June 20th 2018.

Official Title
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Simvastatin in the Prevention of Recurrent Pancreatitis, a Triple Blind, Randomized Controlled Trial

Conditions
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Pancreatitis Relapsing

Intervention / Treatment
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* Drug: Simvastatin 40mg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (>=18) patients At least 2 episodes of acute pancreatitis or acute flares of chronic pancreatitis Written consent to participate in the study Exclusion Criteria: <2 episodes of pancreatitis in the last 12 months. Statin consumption in the previous year. Contraindications to the use of Statins Cholelithiasis or choledocholitiasis diagnosed in the last episode of pancreatitis Endoscopic sphyncterotomy and/or cholecystectomy and/or pancreatic surgery between last episode of AP and recruitment or patients who are expected to undergo one of this techniques in less than a year. Serum triglycerides >500 mg/dL without previous specific treatment before the last episode of pancreatitis, or in patients expected to have a change in their specific hypertriglyceridemia treatment in less than 1 year Primary hyperparathyroidism that has been operated between last episode of pancreatitis and recruitment or will be operated in less than 1 year Iatrogenic Pancreatitis Abstinence syndrome due to alcohol or drugs and/or delirium tremens in the last 6 months before recruitment Previous (last year) failure to attend follow-up medical visits, social problems that may be associated to failure to take the medication or to perform an adequate follow-up Pregnancy, breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>placebo 1 year | Other: Placebo<br>* phase III, triple-blind randomised placebo-controlled trial comparing simvastatin 40 mg/day versus placebo (lactose). One hundred and fifty eight patients with recurrent AP (at least 2 episodes) will be included (79 per arm of treatment). Treatment and follow-up will last for 12 months.<br>* Other names: lactose (brand name: lactosa monohidrato Fagrón);|
| Experimental: Simvastatin<br>40 mg 1 year | Drug: Simvastatin 40mg<br>* phase III, triple-blind randomised placebo-controlled trial comparing simvastatin 40 mg/day versus placebo (lactose). One hundred and fifty eight patients with recurrent AP (at least 2 episodes) will be included (79 per arm of treatment). Treatment and follow-up will last for 12 months.<br>* Other names: Brand name: Simvastatin Normon, 40 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary end point | Recurrence of pancreatitis during the follow-up period. Pancreatitis is defined as 2 or more of the following criteria: I) increased amylase and/or lipase in blood higher than 3 times the upper limit of normality, II) typical abdominal pain and III) signs of acute pancreatitis or acute flare of inflammation in chronic pancreatitis on imaging (CT scan or MRI). | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary end point | New-onset diabetes at the end of follow-up, according to the American Diabetes Association criteria. Blood levels of glycosylated hemoglobin at the end of follow-up will also be compared to baseline (beginning of the study) | 1 year | 
| New-onset exocrine pancreatic insufficiency | New-onset exocrine pancreatic insufficiency defined by fecal elastase-1 <100 mcg/g. Fecal elastase-1 levels at the end of follow-up will also be compared to baseline | 1 year | 
| Chronic Pancreatitis on imaging | Chronic Pancreatitis on imaging at the end of follow-up, defined as calcifications and/or dilated pancreatic duct (≥4mm) on a CT scan | 1 year | 
| All-cause hospital admissions | Frequency of all-cause hospital admissions | 1 year | 
| Severity of pancreatitis | Severity of pancreatitis according to the revision of the Atlanta Classification (moderate-to-severe versus mild) | 1 year | 
| Adherence to treatment | Percentage of the planned treatment consumed by the patient | 1 year | 
| Adverse events | Frequency of adverse events | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatitis, Acute pancreatitis, Chronic pancreatitis, Simvastatin, Recurrent