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Multicenter Prospective Randomized Trial of the Effect of Rivaroxaban on Survival and Development of Complications of Portal Hypertension in Patients With Cirrhosis (CIRROXABAN)

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ClinicalTrials.gov Identifier: NCT02643212
Recruitment Status : Recruiting
First Posted : December 31, 2015
Last Update Posted : April 25, 2018
Sponsor:
Collaborator:
IDIBAPS - Dr. Juan Carlos García Pagán
Information provided by (Responsible Party):
David Garcia Cinca, Hospital Clinic of Barcelona

Tracking Information
First Submitted Date  ICMJE October 26, 2015
First Posted Date  ICMJE December 31, 2015
Last Update Posted Date April 25, 2018
Actual Study Start Date  ICMJE May 2016
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 25, 2016)
Survival free of transplant and decompensation / complications of portal hypertension. [ Time Frame: At month 24 ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 28, 2015)
Survival free of transplant [ Time Frame: At month 24 ]
Change History Complete list of historical versions of study NCT02643212 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 29, 2016)
  • Cirrhosis progression disease (bleeding episode, encephalopathy, ascitis) [ Time Frame: At month 24 ]
    1. Bleeding episode due to portal hypertension.
    2. Hepatic encephalopathy grade II or higher.
    3. 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 [ Time Frame: At month 24 ]
  • To evaluate the efficacy in preventing complications of portal hypertension [ Time Frame: At month 24 ]
    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 [ Time Frame: At month 24 ]
    Evaluate number of bleeding episodes, hematocrit values and number of adverse events and reactions.
  • To evaluate the incidence of hepatocellular carcinoma [ Time Frame: At month 24 ]
    Incidence of hepatocellular carcinoma by semiannual ultrasound.
  • Effect on splenic and liver elasticity measured by fibroscan and / or acoustic radiation force impulse. [ Time Frame: At month 24 ]
    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. [ Time Frame: At month 24 ]
  • 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. [ Time Frame: At month 24 ]
    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 [ Time Frame: At month 24 ]
    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 [ Time Frame: At month 24 ]
    Assess Rivaroxaban reduces bacterial translocation and proinflammatory cytokines. Correlation with clinical events.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 28, 2015)
  • Cirrhosis progression disease (bleeding episode, encephalopathy, ascitis) [ Time Frame: At month 24 ]
    1. Bleeding episode due to portal hypertension.
    2. Hepatic encephalopathy grade II or higher.
    3. 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 [ Time Frame: At month 24 ]
  • To evaluate the efficacy in preventing complications of portal hypertension [ Time Frame: At month 24 ]
    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 [ Time Frame: At month 24 ]
    Evaluate number of bleeding episodes, hematocrit values and number of adverse events and reactions.
  • To evaluate the incidence of hepatocellular carcinoma [ Time Frame: At month 24 ]
    Incidence of hepatocellular carcinoma by semiannual ultrasound.
  • Effect on splenic and liver elasticity mesured by fibroscan and / or acoustic radiation force impulse. [ Time Frame: At month 24 ]
    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. [ Time Frame: At month 24 ]
  • 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. [ Time Frame: At month 24 ]
    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 [ Time Frame: At month 24 ]
    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 [ Time Frame: At month 24 ]
    Assess Rivaroxaban reduces bacterial translocation and proinflammatory cytokines. Correlation with clinical events.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Multicenter Prospective Randomized Trial of the Effect of Rivaroxaban on Survival and Development of Complications of Portal Hypertension in Patients With Cirrhosis
Official Title  ICMJE Not Provided
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Cirrhosis
Intervention  ICMJE
  • Drug: Rivaroxaban
  • Drug: Placebo
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo
  • Experimental: Rivaroxaban
    Rivaroxaban 10mg, 1 once a day
    Intervention: Drug: Rivaroxaban
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 28, 2015)
160
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2019
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Juan Carlos García Pagan, MD +34 93 227 54 00
Contact: David Garcia Cinca +34 93 227 54 00 dgarcia@clinic.ub.es
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02643212
Other Study ID Numbers  ICMJE 2014-005523-27
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party David Garcia Cinca, Hospital Clinic of Barcelona
Study Sponsor  ICMJE David Garcia Cinca
Collaborators  ICMJE IDIBAPS - Dr. Juan Carlos García Pagán
Investigators  ICMJE Not Provided
PRS Account Hospital Clinic of Barcelona
Verification Date April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP