Patients with decompensated cirrhosis MedDRA version: 20.0 Level: LLT Classification code 10009209 Term: Cirrhosis bilary System Organ Class: 100000004871
Conditions
Sponsors
IDIBAPS
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients included into the study must meet all the following criteria: 1. Age = 18 years old. 2. Cirrhosis defined by standard clinical criteria, ultrasonographic findings and/or histology. Cirrhosis of any aetiology may be included. However, patients with cirrhosis due to autoimmune hepatitis must be on stable corticosteroid dose for =3-month period before study inclusion. 3. Child-Pugh B patients or Child-Pugh C patients (up to 12 points). 4. 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**(only if refraining from heterosexual intercourse during the period of twelve months of duration of the study and extended to 30 days after the end of the study treatment). ** Sexual abstinence should only be used as a contraceptive method if it is in line with the subjects’ usual and preferred lifestyle. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 240 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 240
Exclusion criteria
Exclusion criteria: Potential participants who meet any of the following criteria will be excluded from participation in this study: 1. Patients on treatment with statins or rifaximin up to one month before study inclusion. 2. Patients with contraindications for statins or rifaximin therapy. 3. Known hypersensitivity to simvastatin or rifaximin (or rifamycin derivatives). 4. Patients with CK elevation of 50% or more above the upper limit of normal at study inclusion. 5. Patients on treatment with potent inhibitors of CYP3A4 enzyme (see section 5.2: Concomitant, nonpermitted and permitted medication). 6. Patients on treatment with drugs with potential interactions with simvastatin (see section 5.2: Concomitant, nonpermitted and permitted medication). 7. Patients with previous history of myopathy. 8. Patients with previous history of intestinal obstruction or those who are at increased risk of this complication. 9. Patients with ACLF according to the criteria published by Moreau et al. (see appendix 2). 10. Serum creatinine =2 mg/dL (176.8 µmol/L). 11. Serum bilirubin>5 mg/dL (85.5 µmol/L). 12. INR =2.5. Patients under anticoagulant therapy will be excluded if the INR values are = 3.5 13. Bacterial infection within 10 days before study inclusion. 14. Gastrointestinal bleeding within 10 days before study inclusion. 15. Current overt hepatic encephalopathy, defined as grade II-IV hepatic encephalopathy according to the New-Haven classification. 16. 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. 17. Patients on antiviral therapy for HCV or those who have received it within the last 6 months. 18. Severe alcoholic hepatitis requiring corticosteroid therapy (Maddrey’s Discriminant function = 32 and/or ABIC score > 6.7). 19. Patients with active alcohol consumption of more than 21 units per week. 20. HIV infection. 21. 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. 22. Patients with current extra hepatic malignancies including solid tumours and hematologic disorders. 23. Pregnancy or breastfeeding. 24. Patients included in other clinical trials in the month before inclusion. 25. 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. 26. Refusal to give informed consent. 27. Creatinine clearance < 30 ml/min 28. Patients with cirrhosis due to cholestatic liver disease can only be included in the study if they present clinical decompensation of cirrhosis (i.e. ascites). 29. Patients with previous organ transplantation.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of oral administration of Simvastatin plus Rifaximin in halting the progression of decompensated cirrhosis as assessed by the time to first incidence of ACLF during treatment period.;Secondary Objective: -Time to transplant-free survival and incidence -Severity of ACLF -Frequency of hospital admissions due to complications of cirrhosis -Development/worsening of complications of cirrhosis -Systemic inflammatory response -Plasma and urine levels of biomarkers -Vasoactive hormones -Blood levels of bacterial DNA -Changes in fecal microbiome composition -Liver function, evaluated by MELD CLIF-C AD and Child-Pugh Scores -Quality of life, functional assessment and minimal hepatic encephalopathy, as assessed by CLDQ , Liver Frailty score and PHES questionnaires -Stigmatization in patients as assessed by a specific questionnaire -Appearance of muscle toxicity assessed by specific statin-associated myopathy questionnaire -Genetic polymorphisms of statins membrane transporter OATP1B1 -Muscle or liver toxicity assessed by analytical changes -Type and severity of treatment-related adverse events -Annualized incidence of ACLF -Time to overall and time to disease related survival;Primary end point(s): Time to ACLF in the two groups during follow-up..;Timepoint(s) of evaluation of this end point: months 1, 3, 6, 9 and 12 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): -Time to transplant-free survival. Incidences at 1 month, 3 months, 6 months, 9 months and 12 months -Severity of ACLF assessed by number and types of organ failures at baseline, 1 month, 3 months, 6 months, 9 months and 12 months -Frequency of hospital admissions due to complications of cirrhosis assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months -Development/worsening of individual complications of cirrhosis (ascites, acute kidney injury, gastrointestinal bleeding, hepatic encephalopathy (HE), bacterial infections) assessed at baseline and at 1, 3, 6, 9 and 12 months -Changes from baseline in systemic inflammatory response, evaluated by measurement in a large array of plasma cytokine levels including, but not limited to TNFa, IL-6, IL8, IL-10, IL-1ß, IFN-?, G-CSF, VCAM, VEGF, as well as an oxidized form of albumin, human nonmercaptalbumin-2 (HNA2), dimethylarginine (ADMA and SDMA) at 3, 6 and 12 months -Changes from baseline in plasma biomarkers (FABP4, sCD-163), von Willebrand factor (vWF) and urine biomarkers (NGAL, MCP-1, and albumin) at 3 , 6 and 12 months -Changes from baseline in vasoactive hormones: plasma renin concentration, plasma norepinephrine and plasma copeptin at 3, 6 and 12 months -Changes from baseline in blood levels of bacterial DNA or bacterial products at 3, 6 and 12 months -To evaluate changes in microbiome composition by analysis of microbial genes and signature in patients included in the study at baseline and 3, 6 and 12 months -Changes from baseline in liver function, evaluated by MELD score, CLIF-AD score and Child Pugh Score at 1 3, 6, 9 and 12 months. -Quality of life, functional assessment and in Minimal Hepatic Encephalopathy during treatment period, as assessed by CLDQ, Liver Frailty Index and PHES questionnaires at baseline and 1 3, 6, 9 and 12 months -Changes from baseline in stigmatization in patients with decompensated cirrhosis as assessed by a previously validated specific quest | — |
Countries
Belgium, France, Germany, Italy, Netherlands, Spain, United Kingdom
Contacts
Public ContactPere Ginés
Hospital Clínic
Outcome results
None listed