Simvastatin in the Prevention of Recurrent Pancreatitis (SIMBA-16)

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

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

Study Overview

• Status: Terminated
• Conditions: Pancreatitis Relapsing
• Intervention / Treatment: Other: Placebo; Drug: Simvastatin 40mg

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Alicante, Spain, 03010
    • Alicante

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult (>=18) patients
2. At least 2 episodes of acute pancreatitis or acute flares of chronic pancreatitis
3. Written consent to participate in the study

Exclusion Criteria:

1. <2 episodes of pancreatitis in the last 12 months.
2. Statin consumption in the previous year.
3. Contraindications to the use of Statins
4. Cholelithiasis or choledocholitiasis diagnosed in the last episode of pancreatitis
5. 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.
6. 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
7. Primary hyperparathyroidism that has been operated between last episode of pancreatitis and recruitment or will be operated in less than 1 year
8. Iatrogenic Pancreatitis
9. Abstinence syndrome due to alcohol or drugs and/or delirium tremens in the last 6 months before recruitment
10. 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
11. Pregnancy, breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; placebo 1 year	Other: Placebo; 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.; Other Names: lactose (brand name: lactosa monohidrato Fagrón)
Experimental: Simvastatin; 40 mg 1 year	Drug: Simvastatin 40mg; 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.; Other Names: Brand name: Simvastatin Normon, 40 mg

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Enrique de-Madaria
• Collaborators: Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana; Instituto de Salud Carlos III; Generalitat Valenciana
• Investigators: Principal Investigator: Enrique de-Madaria, MD PhD, Gastroenterology Department, Hospital General Universitario de Alicante, Spain

Publications and helpful links

General Publications

• Cardenas-Jaen K, Vaillo-Rocamora A, Gracia A, Garg PK, Zapater P, Papachristou GI, Singh VK, Wu BU, de-Madaria E. Simvastatin in the Prevention of Recurrent Pancreatitis: Design and Rationale of a Multicenter Triple-Blind Randomized Controlled Trial, the SIMBA Trial. Front Med (Lausanne). 2021 Feb 10;7:494. doi: 10.3389/fmed.2020.00494. eCollection 2020.

Study record dates

Study Major Dates

• Study Start (Actual): September 29, 2017
• Primary Completion (Actual): March 1, 2025
• Study Completion (Actual): March 1, 2025

Study Registration Dates

• First Submitted: July 12, 2019
• First Submitted That Met QC Criteria: July 15, 2019
• First Posted (Actual): July 16, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 16, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Simvastatin; Chronic pancreatitis; Recurrent; Acute pancreatitis; Pancreatitis
• Additional Relevant MeSH Terms: Pathologic Processes; Chronic Disease; Disease Attributes; Digestive System Diseases; Pancreatic Diseases; Pancreatitis; Pancreatitis, Chronic; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: SIMBA-16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No