Back to resultsMulticenter Prospective Randomized Trial of the Effect of Rivaroxaban on Survival and Development of Complications of Portal Hypertension in Patients With Cirrhosis (CIRROXABAN)
Primary Purpose
Cirrhosis
Status
Unknown status
Phase
Phase 3
Locations
Spain
Study Type
Interventional
Intervention
Rivaroxaban
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Cirrhosis
Eligibility Criteria
Inclusion Criteria:
- Aged between 18 and 75 years of both sexes.
- Clinical and / or laboratory criteria, ultrasound and / or liver biopsy compatible with the diagnosis of viral cirrhosis (If hepatitis B virus: hepatitis B virus-DNA must be negative; if hepatitis C virus: sustained virologic response should be at least for 6 months prior to enrollment); alcohol (in the last 6 months: in men less than 60 g daily intake in women less than 40 g); nonalcoholic steatohepatitis and cryptogenic.
- Presence of clinically significant portal hypertension defined by clinical criteria (presence of esophageal varices or ascites), elastography (liver Fibroscan® ? 21 kPa) or hemodynamic (Hepatic venous pressure gradient > 10 mmHg)
- Mild to moderate hepatic impairment defined by Child-Pugh of 7-10 points.
- Written informed consent to participate in the study
Exclusion Criteria:
- Any previous or current thrombosis in splenoportal axis (must be ruled out by US-Doppler earlier than one month after randomization; if doubts: computed tomography angiography or magnetic resonance angiography if required).
- Background of hepatic encephalopathy grade II or higher
- Ascites that required prior practice of paracentesis in the last year d. Indication for use of anticoagulant and / or antiplatelet therapy for any reason.
- Hypersensitivity to the active ingredient or to excipients
- Active bleeding, clinically significant, or risk of major bleeding.
- Pregnancy and lactation.
- Hepatocellular carcinoma or malignant neoplasia at the time of inclusion.
- Any comorbidity involving a therapeutic limitation and/or a life expectancy <12 months.
- Existence of risk bleeding esophageal varices or prior variceal bleeding. They may not be included until full treatment (stable beta blockers dosage or eradication trough varices ligation).
- Pregnancy or lactation.
- Severe thrombocytopenia <40,000 platelets / dl.
- Kidney failure (creatinine clearance <15ml / min).
- Transjugular intrahepatic portosystemic shunt or portosystemic shunt carrier.
- Child-Pugh score greater than 10.
- In hepatitis C virus liver cirrhosis patients: not carrying at least six months in sustained virologic response. In hepatitis B virus liver cirrhosis patients: hepatitis B virus DNA is not negative .
- Active alcoholism (60 g / day in men and 40 in women)
- Use of potent inhibitors of cytochrome cytochrome P450 3A4 (ketoconazole, protease inhibitor antiretroviral treatment in human immunodeficiency virus patients) or cytochrome inductors (rifampicin. Phenytoin ...).
- Participation in another clinical trial
Sites / Locations
- Hospital Universitario Central de AsturiasRecruiting
- Hospital German Trias i Pujol
- Hospital Universitari de BellvitgeRecruiting
- Hospital Universitario Marqués de ValdecillaRecruiting
- Hospital Universitario Puerta de Hierro de Majadahonda
- Hospital de la Santa Creu i Sant Pau.
- Hospital Vall d´Hebron
- Hospital Clínic i Provincial de BarcelonaRecruiting
- Hospital Arnau de VilanovaRecruiting
- Hospital Gregorio Marañón
- Hospital Ramón y CajalRecruiting
- Complejo Hospitalario de Pontevedra_Hospital MonteceloRecruiting
- Hospital Universitario Tenerife
- Hospital universitari i politècnic La Fe de Valencia
Arms of the Study
Arm 1
Arm 2
Arm Type
Placebo Comparator
Experimental
Arm Label
Placebo
Rivaroxaban
Arm Description
Rivaroxaban 10mg, 1 once a day
Outcomes
Primary Outcome Measures
Survival free of transplant and decompensation / complications of portal hypertension.
Is defined as decompensation / complications of portal hypertension:
significant bleeding episode (defined as Baveno V) by portal hypertension (esophageal varices, gastric varices; gastropathy Portal Hypertension)
Hepatic encephalopathy grade II or higher.
decompensation of ascites: In patients without ascites decompensation be considered the onset of clinically detectable ascites and confirmed by utrasounds de novo; whereas in those with previous ascites will be considered end-point for worsening ascites if required: a) perform two or more paracentesis evacuator in the next 6 months, or b) the completion of a Transjugular intrahepatic portosystemic shunt.
Secondary Outcome Measures
Cirrhosis progression disease (bleeding episode, encephalopathy, ascitis)
Bleeding episode due to portal hypertension.
Hepatic encephalopathy grade II or higher.
Ascitic decompensation: In patients without ascites, decompensation defined as "de novo" clinically detectable ascites; whereas in those with previous ascites is considered end-point for worsening ascites if required: a) perform two or more evacuative paracentesis in the following six months, or b) the completion of a TIPS
Development of portal vein thrombosis detected by ultrasound and confirmed by CT angiography or MRI angiography
To evaluate the efficacy in preventing complications of portal hypertension
Development of complications of portal hypertension (anamnesis, physical examination, ultrasound and fibrogastroscopy)
Security of rivaroxaban in patients with liver cirrhosis, number of adverse events and adverse reactions in each arm of study. History and clinical evaluation of bleeding and monitoring of hematocrit. Evaluation of liver function
Evaluate number of bleeding episodes, hematocrit values and number of adverse events and reactions.
To evaluate the incidence of hepatocellular carcinoma
Incidence of hepatocellular carcinoma by semiannual ultrasound.
Effect on splenic and liver elasticity measured by fibroscan and / or acoustic radiation force impulse.
Effect of rivaroxaban on liver fibrosis assessed by liver elastography measured by fibroscan and / or acoustic radiation force impulse at baseline and every six months conditions.
Effect of Rivaroxaban on hepatocellular function estimated by the Child-Pugh and the model for end-stage liver disease scores.
To correlate levels of anti-factor Xa and Rivaroxaban on survival free of transplant, cirrhosis progression disease (bleeding episode, encephalopathy, ascitis) and number of adverse events and reactions.
To correlate levels of Rivaroxaban and anti-factor Xa to the efficacy and safety of the drug. Rivaroxaban
To evaluate the effect of Rivaroxaban on hepatic venous pressure gradient
Effect on hepatic venous pressure gradient. Determination of hepatic venous pressure gradient at baseline and 12 months rivaroxaban or placebo
To assess if Rivaroxaban reduces concentration of intestinal fatty acid binding protein, 16S ribosomal DNA, CD14, interleukin 6, lipopolysaccharide binding protein and lipopolysaccharide
Assess Rivaroxaban reduces bacterial translocation and proinflammatory cytokines. Correlation with clinical events.
Full Information
NCT ID
NCT02643212
First Posted
October 26, 2015
Last Updated
April 24, 2018
Sponsor
David Garcia Cinca
Collaborators
IDIBAPS - Dr. Juan Carlos García Pagán
1. Study Identification
Unique Protocol Identification Number
NCT02643212
Brief Title
Multicenter Prospective Randomized Trial of the Effect of Rivaroxaban on Survival and Development of Complications of Portal Hypertension in Patients With Cirrhosis
Acronym
CIRROXABAN
Study Type
Interventional
2. Study Status
Record Verification Date
April 2018
Overall Recruitment Status
Unknown status
Study Start Date
May 2016 (Actual)
Primary Completion Date
December 2019 (Anticipated)
Study Completion Date
December 2019 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
David Garcia Cinca
Collaborators
IDIBAPS - Dr. Juan Carlos García Pagán
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The main objective of the study will determine if patients with liver cirrhosis, anticoagulation free survival improves hypertension decompensation portal and / or transplantation without serious side effects. For it is conduct a double-blind multicenter clinical trial in which patients will be randomized to receive Rivaroxaban or placebo. It included 160 patients with liver cirrhosis and insufficiency mild to moderate hepatic. It will also analyze and develop secondary endpoint portal vein thrombosis. The confirmation of our hypothesis would lead to a radical change in treatment of patients with cirrhosis include treatment with Rivaroxaban in its drove.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cirrhosis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
160 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Title
Rivaroxaban
Arm Type
Experimental
Arm Description
Rivaroxaban 10mg, 1 once a day
Intervention Type
Drug
Intervention Name(s)
Rivaroxaban
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Survival free of transplant and decompensation / complications of portal hypertension.
Description
Is defined as decompensation / complications of portal hypertension:
significant bleeding episode (defined as Baveno V) by portal hypertension (esophageal varices, gastric varices; gastropathy Portal Hypertension)
Hepatic encephalopathy grade II or higher.
decompensation of ascites: In patients without ascites decompensation be considered the onset of clinically detectable ascites and confirmed by utrasounds de novo; whereas in those with previous ascites will be considered end-point for worsening ascites if required: a) perform two or more paracentesis evacuator in the next 6 months, or b) the completion of a Transjugular intrahepatic portosystemic shunt.
Time Frame
At month 24
Secondary Outcome Measure Information:
Title
Cirrhosis progression disease (bleeding episode, encephalopathy, ascitis)
Description
Bleeding episode due to portal hypertension.
Hepatic encephalopathy grade II or higher.
Ascitic decompensation: In patients without ascites, decompensation defined as "de novo" clinically detectable ascites; whereas in those with previous ascites is considered end-point for worsening ascites if required: a) perform two or more evacuative paracentesis in the following six months, or b) the completion of a TIPS
Time Frame
At month 24
Title
Development of portal vein thrombosis detected by ultrasound and confirmed by CT angiography or MRI angiography
Time Frame
At month 24
Title
To evaluate the efficacy in preventing complications of portal hypertension
Description
Development of complications of portal hypertension (anamnesis, physical examination, ultrasound and fibrogastroscopy)
Time Frame
At month 24
Title
Security of rivaroxaban in patients with liver cirrhosis, number of adverse events and adverse reactions in each arm of study. History and clinical evaluation of bleeding and monitoring of hematocrit. Evaluation of liver function
Description
Evaluate number of bleeding episodes, hematocrit values and number of adverse events and reactions.
Time Frame
At month 24
Title
To evaluate the incidence of hepatocellular carcinoma
Description
Incidence of hepatocellular carcinoma by semiannual ultrasound.
Time Frame
At month 24
Title
Effect on splenic and liver elasticity measured by fibroscan and / or acoustic radiation force impulse.
Description
Effect of rivaroxaban on liver fibrosis assessed by liver elastography measured by fibroscan and / or acoustic radiation force impulse at baseline and every six months conditions.
Time Frame
At month 24
Title
Effect of Rivaroxaban on hepatocellular function estimated by the Child-Pugh and the model for end-stage liver disease scores.
Time Frame
At month 24
Title
To correlate levels of anti-factor Xa and Rivaroxaban on survival free of transplant, cirrhosis progression disease (bleeding episode, encephalopathy, ascitis) and number of adverse events and reactions.
Description
To correlate levels of Rivaroxaban and anti-factor Xa to the efficacy and safety of the drug. Rivaroxaban
Time Frame
At month 24
Title
To evaluate the effect of Rivaroxaban on hepatic venous pressure gradient
Description
Effect on hepatic venous pressure gradient. Determination of hepatic venous pressure gradient at baseline and 12 months rivaroxaban or placebo
Time Frame
At month 24
Title
To assess if Rivaroxaban reduces concentration of intestinal fatty acid binding protein, 16S ribosomal DNA, CD14, interleukin 6, lipopolysaccharide binding protein and lipopolysaccharide
Description
Assess Rivaroxaban reduces bacterial translocation and proinflammatory cytokines. Correlation with clinical events.
Time Frame
At month 24
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Aged between 18 and 75 years of both sexes.
Clinical and / or laboratory criteria, ultrasound and / or liver biopsy compatible with the diagnosis of viral cirrhosis (If hepatitis B virus: hepatitis B virus-DNA must be negative; if hepatitis C virus: sustained virologic response should be at least for 6 months prior to enrollment); alcohol (in the last 6 months: in men less than 60 g daily intake in women less than 40 g); nonalcoholic steatohepatitis and cryptogenic.
Presence of clinically significant portal hypertension defined by clinical criteria (presence of esophageal varices or ascites), elastography (liver Fibroscan® ? 21 kPa) or hemodynamic (Hepatic venous pressure gradient > 10 mmHg)
Mild to moderate hepatic impairment defined by Child-Pugh of 7-10 points.
Written informed consent to participate in the study
Exclusion Criteria:
Any previous or current thrombosis in splenoportal axis (must be ruled out by US-Doppler earlier than one month after randomization; if doubts: computed tomography angiography or magnetic resonance angiography if required).
Background of hepatic encephalopathy grade II or higher
Ascites that required prior practice of paracentesis in the last year d. Indication for use of anticoagulant and / or antiplatelet therapy for any reason.
Hypersensitivity to the active ingredient or to excipients
Active bleeding, clinically significant, or risk of major bleeding.
Pregnancy and lactation.
Hepatocellular carcinoma or malignant neoplasia at the time of inclusion.
Any comorbidity involving a therapeutic limitation and/or a life expectancy <12 months.
Existence of risk bleeding esophageal varices or prior variceal bleeding. They may not be included until full treatment (stable beta blockers dosage or eradication trough varices ligation).
Pregnancy or lactation.
Severe thrombocytopenia <40,000 platelets / dl.
Kidney failure (creatinine clearance <15ml / min).
Transjugular intrahepatic portosystemic shunt or portosystemic shunt carrier.
Child-Pugh score greater than 10.
In hepatitis C virus liver cirrhosis patients: not carrying at least six months in sustained virologic response. In hepatitis B virus liver cirrhosis patients: hepatitis B virus DNA is not negative .
Active alcoholism (60 g / day in men and 40 in women)
Use of potent inhibitors of cytochrome cytochrome P450 3A4 (ketoconazole, protease inhibitor antiretroviral treatment in human immunodeficiency virus patients) or cytochrome inductors (rifampicin. Phenytoin ...).
Participation in another clinical trial
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Juan Carlos García Pagan, MD
Phone
+34 93 227 54 00
First Name & Middle Initial & Last Name or Official Title & Degree
David Garcia Cinca
Phone
+34 93 227 54 00
Email
dgarcia@clinic.ub.es
Facility Information:
Facility Name
Hospital Universitario Central de Asturias
City
Oviedo
State/Province
Asturias
ZIP/Postal Code
33011
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Carmen Alvarez-Navascués
Facility Name
Hospital German Trias i Pujol
City
Badalona
State/Province
Barcelona
ZIP/Postal Code
08916
Country
Spain
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Betty Paola Morales
Facility Name
Hospital Universitari de Bellvitge
City
Hospitalet de Llobregat
State/Province
Barcelona
ZIP/Postal Code
08907
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
José Castellote
Facility Name
Hospital Universitario Marqués de Valdecilla
City
Santander
State/Province
Cantabria
ZIP/Postal Code
39008
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Angela Puente
Facility Name
Hospital Universitario Puerta de Hierro de Majadahonda
City
Majadahonda
State/Province
Madrid
ZIP/Postal Code
28222
Country
Spain
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
José Luis Calleja
Facility Name
Hospital de la Santa Creu i Sant Pau.
City
Barcelona
ZIP/Postal Code
08025
Country
Spain
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Càndid Villanueva
Facility Name
Hospital Vall d´Hebron
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joan Genescà
Facility Name
Hospital Clínic i Provincial de Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Juan Carlos Garcia-Pagan, MD
Facility Name
Hospital Arnau de Vilanova
City
Lérida
ZIP/Postal Code
25198
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Carles Aracil
Facility Name
Hospital Gregorio Marañón
City
Madrid
ZIP/Postal Code
28007
Country
Spain
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rafael Bañares
Facility Name
Hospital Ramón y Cajal
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Agustin Albillos
Facility Name
Complejo Hospitalario de Pontevedra_Hospital Montecelo
City
Pontevedra
ZIP/Postal Code
36471
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Juan Turnes
Facility Name
Hospital Universitario Tenerife
City
Tenerife
ZIP/Postal Code
38320
Country
Spain
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Manuel Hernández-Guerra de Aguilar
Facility Name
Hospital universitari i politècnic La Fe de Valencia
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
María Berenguer
12. IPD Sharing Statement
Learn more about this trial
Multicenter Prospective Randomized Trial of the Effect of Rivaroxaban on Survival and Development of Complications of Portal Hypertension in Patients With Cirrhosis
We'll reach out to this number within 24 hrs