Study About Simvastatin in Portal Hypertension in Compensated Cirrhosis (SIMPRO)

Prevention of Progression of Portal Hypertension in Compensated Cirrhosis Using Selective Hepatic Vasodilators. A Double-blind, Multicenter,Randomized Controlled Trial

The purpose of this study is to determine whether simvastatin is effective in the prevention of progression of porta hypertension in compensated cirrhosis patients.

Study Overview

• Status: Unknown
• Conditions: Liver Cirrhosis; Portal Hypertension.
• Intervention / Treatment: Drug: Simvastatin; Drug: placebo

Detailed Description

Decompensation of cirrhosis is associated with a dramatic reduction of survival. Progression of portal hypertension (PHT) is the main determinant of decompensation that appears when portal pressure gradient (PPG) is ≥10mmHg (clinically significant HTP). 40% of compensated cirrhotic patients have mild PHT. However, with progression of disease 41% develop clinically significant PHT. In cirrhosis, PHT results from increased resistance to blood flow, with a dynamic component due to decreased nitric oxide (NO) bioavailability. In advanced disease increased portal venous inflow also contributes to PHT. Beta-blockers have not been useful in compensated cirrhosis with mild PHT. In early cirrhosis, vasodilators may be more adequate. Statins, drugs that inhibit the activity of HMG-CoA reductase, induce selective hepatic vasodilation due to an enhanced bioavailability of NO. Acutely, they decreases hepatic resistance, while with long-term use statins decreases PPG without deleterious effects on systemic circulation. This multicenter, randomized, double-blind placebo-controlled study is aimed at assessing whether treatment with simvastatin may prevent progression of mild PHT (with PPG between 6 and 10 mmHg) to clinically significant PHT. Patients with compensated cirrhosis, without previous decompensation, without esophageal varices at risk and with PPG between 6 and 10 mmHg will be included. The calculated sample size is 80 patients and the duration of the study 4 years (2 years including and a follow-up of at least 2 year).

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Candido Villanueva, PHD; Phone Number: 935565917; Email: cvillanueva@santpau.cat
• Study Contact Backup: Name: Angela Puente, MD; Phone Number: 935565917; Email: apuentesa@santpau.cat

Study Locations

• Spain
  • Barcelona, Spain, 08025
    • Hospital de La Santa Creu i Sant Pau
    • Principal Investigator: Candido Villanueva, mPHD
    • Sub-Investigator: Angela Puente, PHD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Liver cirrhosis diagnosed by previous biopsy or by clinical, laboratory, ultrasound
• Portal hypertension gradient between6 mmHg and10 mmHg
• Absence of esophageal and gastric varices or small esophageal varices without red signs
• Absence previous episodes of gastrointestinal hemorrhage, ascites, encephalopathy or jaundice
• Written informed consent

Exclusion Criteria:

• Age <18 and> 80 years,
• Presence or history of ascites, clinical or ultrasound,
• Previous decompensation of liver cirrhosis, ascites or SBP, bleeding varices, large varices, hepatic encephalopathy, jaundice,
• Thrombosis splenoportal,
• Hepatocellular carcinoma;
• Child-Pugh >7 point
• Any comorbidity that leads to a restriction therapy and / or a life expectancy <12 months
• Absolute contraindication to treatment with statins or allergy Simvastatin;
• Concomitant potent CYP3A4 inhibitors (eg., itraconazole, ketoconazole, protease inhibitors, HIV, erythromycin, clarithromycin, telithromycin and nefazodone),
• Pretreatment (<1 month) with simvastatin or other lipid-lowering,
• Previous episodes of rhabdomyolysis,
• Active alcoholic hepatitis,
• Refusal to participate in the study or the informed consent claim;
• Pre-treatment with beta blockers or nitrates, or endoscopic treatment for varicose veins or portosystemic derivations;
• Pregnancy and lactation.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: simvastatin; The experimental group will take simvastatin 40mg for at least two years.	Drug: Simvastatin; The experimental group will take 40 mg each 24 hours for at least two years.
Placebo Comparator: placebo; the control group wiil take placebo pills for at least two years.	Drug: placebo; the control group wiil take placebo pills for at least two years.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the treatment of portal hypertension with simvastatin may prevent progression of portal hypertension	The main objective is to assess whether, in patients with compensated cirrhosis and mild portal hypertension (GPP between 6 and 10mmHg), the treatment of portal hypertension with simvastatin may prevent progression of portal hypertension and prevent the development of clinically significant HTP (defined GPP by a ≥ 10 mmHg)	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Portal hypertension complications	Development of complications related to portal hypertension (gastrointestinal bleeding related to portal hypertension, ascites, hepatic encephalopathy).	four years
Adverse effects		four years

Collaborators and Investigators

• Sponsor: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
• Collaborators: Instituto de Salud Carlos III

Publications and helpful links

General Publications

• Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, Escorsell A, Garcia-Pagan JC, Patch D, Matloff DS, Gao H, Makuch R; Portal Hypertension Collaborative Group. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. 2005 Nov 24;353(21):2254-61. doi: 10.1056/NEJMoa044456.
• Abraldes JG, Albillos A, Banares R, Turnes J, Gonzalez R, Garcia-Pagan JC, Bosch J. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology. 2009 May;136(5):1651-8. doi: 10.1053/j.gastro.2009.01.043. Epub 2009 Jan 24.
• Villanueva C, Aracil C, Colomo A, Hernandez-Gea V, Lopez-Balaguer JM, Alvarez-Urturi C, Torras X, Balanzo J, Guarner C. Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding. Gastroenterology. 2009 Jul;137(1):119-28. doi: 10.1053/j.gastro.2009.03.048. Epub 2009 Apr 1.
• Zafra C, Abraldes JG, Turnes J, Berzigotti A, Fernandez M, Garca-Pagan JC, Rodes J, Bosch J. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology. 2004 Mar;126(3):749-55. doi: 10.1053/j.gastro.2003.12.007.
• Marrache MK, Rockey DC. Statins for treatment of chronic liver disease. Curr Opin Gastroenterol. 2021 May 1;37(3):200-207. doi: 10.1097/MOG.0000000000000716.

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Anticipated): April 1, 2012
• Study Completion (Anticipated): April 1, 2015

Study Registration Dates

• First Submitted: January 21, 2011
• First Submitted That Met QC Criteria: January 24, 2011
• First Posted (Estimate): January 25, 2011

Study Record Updates

• Last Update Posted (Estimate): January 25, 2011
• Last Update Submitted That Met QC Criteria: January 24, 2011
• Last Verified: January 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Liver Diseases; Fibrosis; Hypertension; Liver Cirrhosis; Hypertension, Portal; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: IIBSP-SIM-2010-06