Efficacy of the Combination of Simvastatin Plus Rifaximin in Patients With Decompensated Cirrhosis to Prevent ACLF Development

Judit Pich254 enrolled

Overview

The aim of this study is to assess the efficacy of oral administration of simvastatin plus rifaximin in patients with decompensated cirrhosis to halt the progression of the disease as assessed by prevention of the development of ACLF

The current study was aimed at assessing whether a treatment based on combination of rifaximin and simvastatin would be effective in patients with decompensated cirrhosis to prevent ACLF development Considering that statins have been scarcely investigated in patients with decompensated cirrhosis due to a concern of potential higher liver and muscle toxicity in this population, a first LIVERHOPE\_SAFETY clinical trial (unpublished) was undergone to assess safety and toxicity of statins with decompensated cirrhosis. As a preliminary result of the LIVERHOPE\_SAFETY clinical trial, it was concluded that the dose of Simvastatin 20mg per day plus Rifaximin is not associated to a higher risk of liver or muscle toxicity in patients with decompensated cirrhosis and simvastatin 20 mg was established for the LIVERHOPE\_EFFICACY study.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

254

Conditions

Liver Cirrhoses

Interventions

SimvastatinDRUG

Simvastatin 20 mg/day for 12 months

RifaximinDRUG

Rifaximin 400/8 hours for 12 months

Placebo of SimvastatinDRUG

Placebo of Simvastatin once a day for 12 months

Placebo of Rifaximin

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age ≥ 18 years old * Cirrhosis defined by standard clinical criteria, ultrasonographic findings and/or histology * Child-Pugh patients or Child-Pugh C patients (up to 12 points) * Women of child-bearing potential must have a negative pregnancy test in serum before the inclusion in the study and agree to use highly effective contraceptive methods during the study. Highly effective contraceptive methods will include: intrauterine device, bilateral tubal occlusion, vasectomized partner and sexual abstinence. Exclusion Criteria: * Patients on treatment with statins or rifaximin up to one month before study inclusion. * Patients with contraindications for statins or rifaximin therapy. * Known hypersensitivity to simvastatin or rifaximin (or rifamycin derivatives). * Patients with CK elevation of 50% or more above the upper limit of normal at study inclusion. * Patients on treatment with potent inhibitors of CYP3A4 enzyme * Patients on treatment with drugs with potential interactions with simvastatin * Patients with previous history of myopathy. * Patients with previous history of intestinal obstruction or those who are at increased risk of this complication. * Patients with ACLF according to the criteria published by Moreau et al. * Serum creatinine ≥2 mg/dL (176.8 μmol/L). * Serum bilirubin\>5 mg/dL (85.5 μmol/L). * 12\. INR ≥2.5 * Bacterial infection within 10 days before study inclusion. * Gastrointestinal bleeding within 10 days before study inclusion. * Current overt hepatic encephalopathy, defined as grade II-IV hepatic encephalopathy according to the New-Haven classification. * Patients with active hepatocellular carcinoma or history of hepatocellular carcinoma that is in remission for less than six months for uninodular HCC or for less than 12 months for multinodular HCC within Milan criteria. * Patients on antiviral therapy for HCV or those who have received it within the last 6 months. * Severe alcoholic hepatitis requiring corticosteroid therapy (Maddrey's Discriminant function ≥ 32 and/or ABIC score \> 6.7). * Patients with active alcohol consumption of more than 21 units per week. * HIV infection. * Patients with a history of significant extra hepatic disease with impaired short-term prognosis, including congestive heart failure New York Heart Association Grade III/IV, COPD GOLD \>2, chronic kidney disease with serum creatinine \>2mg/dL or under renal replacement therapy. * Patients with current extra hepatic malignancies including solid tumours and hematologic disorders. * Pregnancy or breastfeeding. * Patients included in other clinical trials in the month before inclusion. * Patients with mental incapacity, language barrier, bad social support or any other reason considered by the investigator precluding adequate understanding, cooperation or compliance in the study. * Refusal to give informed consent.

Locations (14)

University Hospitals Leuven

Leuven, Belgium

Beajuon Hospital

Clichy, Paris, France

Universitatsklinikum Frankurt

Frankfurt, Germany

Outcomes

Primary Outcomes

Incidence of ACLF at the end of the study

Time frame: Month 12

Secondary Outcomes

Time to transplant-free survival at months1, 3, 6, 9 and 12

Time frame: months 1, 3, 6, 9 and 12

Severity of ACLF assessed by number and types of organ failures at baseline, 1 month, 3 months, 6 months, 9 months and 12 months

Time frame: months 1, 3, 6, 9 and 12

Frequency of hospital admissions due to complications of cirrhosis assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months.

Time frame: baseline and months 1, 3, 6, 9 and 12

Number of participants developing a new onset episode of ascitis assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months

Time frame: baseline and months 1, 3, 6, 9 and 12

Number of participants presenting worsening of ascitis assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months

Worsening of ascitis will be defined as increased diuretic dosage or need for large-volume parecentesis in patients who had never been treated with this procedure

Time frame: baseline and months 1, 3, 6, 9 and 12

Percentage of participants developing episodes of renal function impairment assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months

Renal function impairment will be defined by AKI criteria, following criteria of the "EASL Clinical Practice Guidelines for the management of patients with decompensated cirrosis"

Time frame: baseline and months 1, 3, 6, 9 and 12

Percentage of participants developing the first episode of bleeding by esophageal or gastric varices at baseline, 1 month, 3 months, 6 months, 9 months and 12 months

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Placebo of Rifaximin/8 hours for 12 months

Bologna University Hospital

Bologna, Italy

Padova University Hospital

Padova, Italy

San Giovanni Battista Hospital

Torino, Italy

Academic Medical Centre

Amsterdam, Netherlands

Hospital Clínic de Barcelona

Barcelona, España, Spain

Hospital Universitari Vall d'Hebrón

Barcelona, Spain

Hospital de Sant Pau

Barcelona, Spain

...and 4 more locations

Time frame: baseline and months 1, 3, 6, 9 and 12

Number of bleeding episodes by esophageal or gastric varices per patient assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months

Time frame: baseline and months 1, 3, 6, 9 and 12

Number of participants developing a new onset episode of hepatic encephalopathy (HE) assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months

Time frame: baseline and months 1, 3, 6, 9 and 12

Number of participants developing a new onset episode of bacterial infection assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months

Time frame: baseline and months 1, 3, 6, 9 and 12

Changes from baseline in plasma cytokine levels including, but not limited to, TNFα at 3 months, 6 months and 12 months