Patients with decompensated cirrhosis MedDRA version: 19.1 Level: PT Classification code 10019641 Term: Hepatic cirrhosis System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Sponsors
IDIBAPS
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age = 18 years old. 2. Cirrhosis defined by standard clinical criteria and ultrasonographic findings and/or histology. Cirrhosis of any etiology may be included. Patients with cirrhosis of autoimmune etiology on treatment with corticosteroids must be on stable corticosteroid dose for =3-month period before study inclusion. 3. Child Pugh B/C patients (from 7 to 12 points). 4. Women of child-bearing potential must have a negative pregnancy test in urine before the inclusion of the study and agree to use highly effective contraceptive methods (combined oral pill, injectable or implanted contraceptive, intrauterine device / intrauterine hormone-releasing system) during the study. 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 45 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 45
Exclusion criteria
Exclusion criteria: 1. Patients on treatment with statins or rifaximin one month before study inclusion. 2. Patients on the waiting list for liver transplantation. 3. Patients with acute-on-chronic liver failure according to the criteria published by Moreau et al. (see appendix 1) 4. Serum creatinine =2 mg/dL. 5. Serum bilirubin>5 mg/dL. 6. INR =2.5. 7. Patients with CK elevation of 50% or more above the upper limit of normal at study inclusion. 8. Bacterial infection within 15 days before study inclusion. 9. Gastrointestinal bleeding within 15 days before study inclusion. 10. Current overt hepatic encephalopathy, defined as grade II-IV hepatic encephalopathy. 11. HIV infection. 12. Hepatocellular carcinoma outside Milan criteria, defined as a single nodule =5 cm or a maximum of 3 nodules with none >3 cm. 13. Patients on antiviral therapy for HCV or those who have received it within the last 6 months. 14. Patients with previous history of myopathy. 15. Patients on treatment with potent inhibitors of CYP3A4 enzyme (See section 5.2: Concomitant, nonpermitted and permitted medication) 16. Patients on treatment with drugs with potential interactions with simvastatin (see section 5.2: Concomitant, nonpermitted and permitted medication) 17. Patients with a history of significant extrahepatic 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. 18. Patients with current extrahepatic malignancies including solid tumours and hematologic disorders. 19. Patients with previous history or increased risk of intestinal obstruction. 20. Pregnancy or breastfeeding. 21. Patients included in other clinical trials in the previous month. 22. Patients with active alcohol consumption of more than 3 units per day. 23. 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. 24. Severe alcoholic hepatitis requiring corticosteroid therapy (Maddrey’s Discriminant function = 32 and/or ABIC score > 6.7). 25. Refusal to give informed consent. 26. Patients with contraindications for statins or rifaximin. 27. Known hypersensitivity to rifaxamin (or rifamycin derivatives) or to simvastatin.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the treatment-related toxicity of oral administration of simvastatin plus rifaximin in patients with decompensated cirrhosis.;Secondary Objective: 1.To evaluate the appearance of muscle toxicity as defined using a statin-associated myopathy questionnaire. 2.To evaluate hormone levels: plasma renin concentration, serum aldosterone, plasma norepinephrine and plasma copeptin. 3. To evaluate systemic inflammatory response by measurement in a large array of plasma cytokine levels during the treatment period. 4.To evaluate levels of plasma biomarkers (FABP4, CD-163) and urine biomarkers (NGAL, IL-18, MCP-1, osteopontin and albumin) during the treatment period. 5.To evaluate blood levels of bacterial DNA or bacterial products during the treatment period. 6.To evaluate genetic polymorphisms of statins membrane transporter OATPB1 in patients developing treatment-related toxicity. 7.To evaluate the treatment-related serious adverse events during the treatment period.;Primary end point(s): Change from baseline in transaminases, alkaline phosphatase and creatine kinase during the treatment period, to evaluate treatment-related toxicity. This quantitative analysis will be complemented by qualitative binary assessment which will consist of: (1) liver toxicity assessed by the development of liver injury defined as 3-fold increase in serum transaminases to a final value at least 3 times the upper normal limit, or 2-fold increase in serum levels of alkaline phosphatase with respect to baseline value to a final value at least 2 times the upper normal limit, or (2) muscle toxicity, defined as 5-fold increase in creatinine kinase (CK) levels during treatment.;Timepoint(s) of evaluation of this end point: 12 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Appearance of muscle toxicity at weeks 2, 4, 6, 8, 10 and 12 as defined using a specific statin-associated myopathy questionnaire (see appendix 2). 2. Changes from baseline in plasma renin concentration, serum aldosterone, plasma norepinephrine, and plasma copeptin levels at weeks 2, 4, 8 and 12. 3. Changes from baseline in a large array of plasma cytokine levels including, but not limited to, VCAM-1, VEGF-A, Fractalkine, MIP-1a, Eotaxin, IP-10, RANTES, GM-CSF, IL-1ß, IL-2, ICAM-1, MCP-1, L-6, and IL-8, as well as an oxidized form of albumin, human nonmercaptalbumin-2 (HNA2) at weeks 2, 4, 8 and 12. 4. Changes from baseline in plasma biomarkers FABP4 and CD-163 and urine biomarkers NGAL, IL-18, MCP-1, osteopontin, and albumin at weeks 2, 4, 8 and 12. 5. Changes in blood levels of bacterial DNA or bacterial products at weeks 2, 4, 8 and 12. 6. Assessment of genetic polymorphisms of statins membrane transporter OATPB1 in patients developing treatment-related toxicity (defined as the primary endpoint of the study). 7. Proportion of patients with treatment-related serious adverse events during the study period.;Timepoint(s) of evaluation of this end point: weeks 2, 4, 6, 7, 10 and 12 | — |
Countries
Netherlands, Spain
Contacts
Public ContactPere Ginés
Hospital Clínic
Outcome results
None listed