Study About Simvastatin in Portal Hypertension in Compensated Cirrhosis

Liver Cirrhosis Clinical Trial

— SIMPRO  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT01282398
• Other study ID #: IIBSP-SIM-2010-06
• Status: Not yet recruiting
• Phase: Phase 4
• First received: January 21, 2011
• Last updated: January 24, 2011
• Start date: April 2011
• Est. completion date: April 2015

Study information

• Verified date: January 2011
• Source: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
• Contact: Candido Villanueva, PHD
• Phone: 935565917
• Email: cvillanueva[@]santpau.cat
• Is FDA regulated: No
• Health authority: Spain: Spanish Agency of Medicines
• Study type: Interventional

Clinical Trial Summary

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

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).

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 80
• Est. completion date: April 2015
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Portal
• Liver Cirrhosis
• Portal Hypertension.

Intervention

Drug:
• Simvastatin
The experimental group will take 40 mg each 24 hours for at least two years.
• placebo
the control group wiil take placebo pills for at least two years.

Locations

Country	Name	City	State
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona

Sponsors (2)

Lead Sponsor	Collaborator
Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau	Instituto de Salud Carlos III

Country where clinical trial is conducted

Spain, 

References & Publications (4)

Abraldes JG, Albillos A, Bañares R, Turnes J, González R, García-Pagán 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: 10.105 — View Citation

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 cirrhos — View Citation

Villanueva C, Aracil C, Colomo A, Hernández-Gea V, López-Balaguer JM, Alvarez-Urturi C, Torras X, Balanzó J, Guarner C. Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding. Gastroente — View Citation

Zafra C, Abraldes JG, Turnes J, Berzigotti A, Fernández M, Garca-Pagán JC, Rodés 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	Portal hypertension complications	Development of complications related to portal hypertension (gastrointestinal bleeding related to portal hypertension, ascites, hepatic encephalopathy).	four years	Yes
Secondary	Adverse effects		four years	Yes