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Efficacy of Statin Association With Standard Treatment in Prevention of Recurrent Hemorrhage in Patient With Cirrhosis and Variceal Bleeding

Primary Purpose

Cirrhosis, Hypertension, Portal, Bleeding Esophageal Varices

Status
Completed
Phase
Phase 3
Locations
Spain
Study Type
Interventional
Intervention
Simvastatin
Placebo
Sponsored by
Juan A. Arnaiz
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cirrhosis

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients between 18 and 80 years old.
  • Clinical criteria and/or analytical, ultrasound and/or liver biopsy consistent with the diagnosis of liver cirrhosis.
  • Hematemesis or melenas within 7 days prior to study inclusion.

  • Variceal bleeding. Endoscopic diagnosis:

    • Active variceal bleeding.
    • Clot or platelet cluster or,
    • Esophageal varices associated to red blood in esophagogastric lumen in the absence of other sources of bleeding.
  • Patients with standard treatment for prevention of recurrence of variceal bleeding (EVL+B Blockers,Propanolol).
  • Women of childbearing age should have a urine pregnancy test negative for 7 days before commencement of treatment and postmenopausal women must have amenorrhea for at least 12 months to be considered not fertile. Potential childbearing women and men must commit to use adequate contraception prior to joining the study and during it.
  • Written informed consent to participate in the study.

Exclusion Criteria:

  • Pregnancy or lactation
  • Presence multiple hepatocellular carcinoma or only diameter> 5 cm.
  • Renal failure ( Creatinine > 2 mg/dl)
  • Advanced liver disfunction (Child Pugh > 13 points)
  • Contraindication for statins.
  • Patients HIV treated with antiretroviral therapy.
  • Pre-treatment with portosystemic shunt ( surgical or percutaneous).
  • Bleeding due to gastric varices.
  • Patients with total portal vein thrombosis or portal cavernomatosis.
  • Patients previously treated with endoscopic variceal ligation and B- Blockers (before index episode).
  • Patients previously treated with statins ( one month before the study).

Sites / Locations

  • Complejo Universitario Central de Asturias
  • Hospital Universitari Bellvitge
  • Corporació Sanitària Parc Tauli
  • Hospital Arnau de Vilanova
  • Complejo Hospitalario Pontevedra
  • Hospital Puerta del Hierro
  • Hospital Universitario de Alicante
  • Hospital Clinic
  • Hospital de la Santa Creu i Sant Pau
  • Hospital German Trias i Pujol
  • Hospital de la Vall d'Hebron
  • Hospital Universitario del Mar
  • Hospital Gregorio Marañon
  • Hospital Ramón y Cajal
  • Hospital Universitario de Canarias

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Standard therapy + Simvastatin

Standard therapy + placebo

Arm Description

Standard therapy: Endoscopic variceal ligation (EVL)+ B Blockers (Propanolol titrated until achieve maximum tolerated dose) Simvastatin (20 mg for 15 days and after 40 mg/day until the end of the study)

Standard therapy: Endoscopic variceal ligation (EVL)+ B Blockers (Propanolol titrated maximum tolerated dose). Placebo

Outcomes

Primary Outcome Measures

Recurrence of variceal bleeding and patient survival

Secondary Outcome Measures

Bleeding severity in both arms.
Appearance or progression of Portal Hypertension complications
Appearance or progression of Portal Vein Thrombosis
Need for alternative treatments (transjugular intrahepatic portosystemic shunt [TIPS], surgery)
Incidence of adverse events of statin treatment

Full Information

First Posted
March 29, 2010
Last Updated
March 18, 2015
Sponsor
Juan A. Arnaiz
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1. Study Identification

Unique Protocol Identification Number
NCT01095185
Brief Title
Efficacy of Statin Association With Standard Treatment in Prevention of Recurrent Hemorrhage in Patient With Cirrhosis and Variceal Bleeding
Official Title
A Randomized, Multicenter,Double Blind,Controlled With Placebo Trial About Efficacy of Statin Association With Standard Treatment in Prevention of Recurrent Hemorrhage in Patient With Liver Cirrhosis and Variceal Bleeding
Study Type
Interventional

2. Study Status

Record Verification Date
March 2015
Overall Recruitment Status
Completed
Study Start Date
November 2010 (undefined)
Primary Completion Date
September 2013 (Actual)
Study Completion Date
September 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Juan A. Arnaiz

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a prospective, double blind controlled trial in which patients with esophagic variceal bleeding treated with standard therapy (endoscopic variceal ligation(EVL) + B-blockers), will be randomized to receive statins or placebo. They will be followed up during 12 months to determinate whether statins are effective in prevention of variceal bleeding recurrence and evaluate patient survival. Randomization will be stratified according to the degree of hepatic insufficiency, assessed by the Child-Pugh classifications (A,B or C).
Detailed Description
A mayor cause of cirrhosis-related morbility and mortality is the development of variceal hemorrhage, a direct consequence of portal hypertension. In addition, survivors of an episode of active bleeding have a 70 % risk of recurrent hemorrhage within two years of the bleeding episode and the highest risk it is situated in the first six weeks after the hemorrhage episode. The recommended treatment in AASLD guidelines is the combination of non selective Betablockers with endoscopic treatment with EVL, with high recurrence (30% in 2 years). The hypothesis of this study is that statins are candidates for improving portal hypertension treatment in patients with cirrhosis, improving vascular function as well as preventing venous thrombotic events. Patients with liver cirrhosis and variceal bleeding with standard treatment will be stratified and after randomized to undergo either statins (20 mg for 15 days, and after 40 mg/day) or placebo. They will be followed up for 12 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cirrhosis, Hypertension, Portal, Bleeding Esophageal Varices, Portal Vein Thrombosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
150 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Standard therapy + Simvastatin
Arm Type
Experimental
Arm Description
Standard therapy: Endoscopic variceal ligation (EVL)+ B Blockers (Propanolol titrated until achieve maximum tolerated dose) Simvastatin (20 mg for 15 days and after 40 mg/day until the end of the study)
Arm Title
Standard therapy + placebo
Arm Type
Placebo Comparator
Arm Description
Standard therapy: Endoscopic variceal ligation (EVL)+ B Blockers (Propanolol titrated maximum tolerated dose). Placebo
Intervention Type
Drug
Intervention Name(s)
Simvastatin
Other Intervention Name(s)
Simvastatina, Simvastatina Ratiopharm
Intervention Description
Simvastatin 20 mg for 15 days, then 40 mg until the end of the study.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Simvastatin placebo
Primary Outcome Measure Information:
Title
Recurrence of variceal bleeding and patient survival
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Bleeding severity in both arms.
Time Frame
12 months
Title
Appearance or progression of Portal Hypertension complications
Time Frame
12 months
Title
Appearance or progression of Portal Vein Thrombosis
Time Frame
12 months
Title
Need for alternative treatments (transjugular intrahepatic portosystemic shunt [TIPS], surgery)
Time Frame
12 months
Title
Incidence of adverse events of statin treatment
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients between 18 and 80 years old. Clinical criteria and/or analytical, ultrasound and/or liver biopsy consistent with the diagnosis of liver cirrhosis. Hematemesis or melenas within 7 days prior to study inclusion. Variceal bleeding. Endoscopic diagnosis: Active variceal bleeding. Clot or platelet cluster or, Esophageal varices associated to red blood in esophagogastric lumen in the absence of other sources of bleeding. Patients with standard treatment for prevention of recurrence of variceal bleeding (EVL+B Blockers,Propanolol). Women of childbearing age should have a urine pregnancy test negative for 7 days before commencement of treatment and postmenopausal women must have amenorrhea for at least 12 months to be considered not fertile. Potential childbearing women and men must commit to use adequate contraception prior to joining the study and during it. Written informed consent to participate in the study. Exclusion Criteria: Pregnancy or lactation Presence multiple hepatocellular carcinoma or only diameter> 5 cm. Renal failure ( Creatinine > 2 mg/dl) Advanced liver disfunction (Child Pugh > 13 points) Contraindication for statins. Patients HIV treated with antiretroviral therapy. Pre-treatment with portosystemic shunt ( surgical or percutaneous). Bleeding due to gastric varices. Patients with total portal vein thrombosis or portal cavernomatosis. Patients previously treated with endoscopic variceal ligation and B- Blockers (before index episode). Patients previously treated with statins ( one month before the study).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jaume Bosch, MD
Organizational Affiliation
Hospital Clínic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Complejo Universitario Central de Asturias
City
Oviedo
State/Province
Asturias
Country
Spain
Facility Name
Hospital Universitari Bellvitge
City
L´Hospitalet del LLobregat
State/Province
Barcelona
Country
Spain
Facility Name
Corporació Sanitària Parc Tauli
City
Sabadell
State/Province
Barcelona
Country
Spain
Facility Name
Hospital Arnau de Vilanova
City
LLeida
State/Province
Catalunya
Country
Spain
Facility Name
Complejo Hospitalario Pontevedra
City
Pontevedra
State/Province
Galicia
Country
Spain
Facility Name
Hospital Puerta del Hierro
City
Majadahonda
State/Province
Madrid
Country
Spain
Facility Name
Hospital Universitario de Alicante
City
Alicante
Country
Spain
Facility Name
Hospital Clinic
City
Barcelona
ZIP/Postal Code
08005
Country
Spain
Facility Name
Hospital de la Santa Creu i Sant Pau
City
Barcelona
ZIP/Postal Code
08041
Country
Spain
Facility Name
Hospital German Trias i Pujol
City
Barcelona
ZIP/Postal Code
089016
Country
Spain
Facility Name
Hospital de la Vall d'Hebron
City
Barcelona
Country
Spain
Facility Name
Hospital Universitario del Mar
City
Barcelona
Country
Spain
Facility Name
Hospital Gregorio Marañon
City
Madrid
Country
Spain
Facility Name
Hospital Ramón y Cajal
City
Madrid
Country
Spain
Facility Name
Hospital Universitario de Canarias
City
Tenerife
Country
Spain

12. IPD Sharing Statement

Citations:
PubMed Identifier
26774179
Citation
Abraldes JG, Villanueva C, Aracil C, Turnes J, Hernandez-Guerra M, Genesca J, Rodriguez M, Castellote J, Garcia-Pagan JC, Torres F, Calleja JL, Albillos A, Bosch J; BLEPS Study Group. Addition of Simvastatin to Standard Therapy for the Prevention of Variceal Rebleeding Does Not Reduce Rebleeding but Increases Survival in Patients With Cirrhosis. Gastroenterology. 2016 May;150(5):1160-1170.e3. doi: 10.1053/j.gastro.2016.01.004. Epub 2016 Jan 14.
Results Reference
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Efficacy of Statin Association With Standard Treatment in Prevention of Recurrent Hemorrhage in Patient With Cirrhosis and Variceal Bleeding

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