reduction of liver fibrosis in patients with advanced fibrosis due to alcohol MedDRA version: 20.1 Level: PT Classification code 10001627 Term: Alcoholic liver disease System Organ Class: 10019805 - Hepatobiliary disorders MedDRA version: 20.0 Level: PT Classification code 10019668 Term: Hepatic fibrosis System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Interventions
Product Name: Simvastatin
Pharmaceutical Form: Coated tablet
INN or Proposed INN: SIMVASTATIN
CAS Number: 79902-63-9
Concentration unit: mg milligram(s)
Concentration type: not less then
Concentration
Sponsors
Institut d’Investigacions Biomèdiques August Pi i Sunyer
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age = 18 years 2. Chronic alcohol-related liver disease according to international guidelines (EASL, European Association for the Study of the Liver) (ishak 3-6)and with data of significant liver fibrosis obtained in the diagnostic biopsy at the beginning of the study or in the last biopsy of the patient within 6 months prior to randomization. Significant liver fibrosis is defined by a score on the Ishak fibrosis scale of between 3 and 6. 3. Patients in the compensated chronic liver disease phase defined by the absence of clinical decompensations at the time of entering the study, with or without data of portal hypertension. 4. Women of childbearing potential must have a negative urine pregnancy test prior to study enrollment and agree to use highly effective contraceptive methods (combined oral pill, injectable or implanted contraceptive, intrauterine device / hormone delivery system intrauterine) 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 75 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 15
Exclusion criteria
Exclusion criteria: 1. Patients receiving statins or fibrates. 2. Patients with other etiologies of liver disease in addition to alcohol: hepatitis C, hepatitis B, autoimmune hepatitis, Wilson's disease, or hemochromatosis. 3. Patients in whom hepatitis C has been cured with antivirals in the 2 years prior to inclusion in the study. 4. Patients with a CK elevation of 50% or more above the upper limit of normal at the time of study inclusion. 5. Gastrointestinal bleeding due to portal hypertension within 12 months prior to inclusion in the study. 6. Clinical hepatic encephalopathy, defined as grade II-IV hepatic encephalopathy, in the 12 months prior to inclusion in the study. 7. Patients in need of diuretic treatment in the previous 12 months to control ascites or hydrothorax. 8. Spontaneous bacterial peritonitis within 12 months prior to study enrollment. 9.Child-Pugh > 8 10. Hepatocellular carcinoma of any stage. 11. Patients with known muscle disease. 12. Patients with previous rhabdomyolysis. 13. Patients being treated with strong CYP3A4 enzyme inhibitors (see section 5.2: Concomitant drugs, not allowed and allowed). 14. Patients being treated with drugs with possible interactions with simvastatin (see section 5.2: Concomitant drugs, not allowed and allowed). 15. Patients with a history of significant extrahepatic disease with poor short-term prognosis, including New York Heart Association Grade III / V congestive heart failure, GOLD COPD> 2, chronic kidney disease with serum creatinine> 2mg / dL or under therapy of kidney replacement. 16. Patients with extrahepatic malignancies, including solid tumors and hematologic malignancies. 17. Patients with a history or increased risk of intestinal obstruction. 18. Pregnancy or breastfeeding. 19. Patients included in other clinical trials during the previous month. 20. Patients with mental disabilities, language barriers, poor social support or any other reason considered by the researcher as essential for adequate understanding, cooperation or compliance with the study. 21. Presence of data on alcoholic hepatitis in liver biopsy upon inclusion. 22. Patients with contraindications for statins. 23. Known hypersensitivity to simvastatin. 24. Refusal to sign the informed consent.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Proportion of patients with a significant reduction in the degree of liver fibrosis after treatment with simvastatin compared to placebo, analyzed through the histological evaluation of fibrosis using the Ishak scale, defined as a reduction in the fibrosis value of at least one point on the scale;Secondary Objective: 1. Analyze the effect of simvastatin on liver fibrosis applied by non-invasive methods: a. Transient liver elastography. B. Magnetic resonance elastography (MRA). C. Serum markers and liver fibrosis score validated for ALD 2. Study the changes in liver fibrosis and other histological parameters of the disease: a. Liver fibrosis B. "Proportional area of ??collagen" C. Histological parameters of chronic alcoholic liver disease 3. Study the effect of simvastatin on the intestinal microbiota. 4. Analyze the markers of systemic inflammation, immune response, bacterial translocation and endothelial dysfunction: a. Proinflammatory cytokines B. Bacterial translocation markers C. Markers of endothelial dysfunction D. Inflammatory profile of circulating immune cells: lymphocytes, monocytes, and neutrophils. 5. Describe the incidence of adverse effects and the safety of the treatment.;Primary end point(s): Proportion of patients with a significant reduction in the degree of liver fibrosis after treatment with simvastatin compared to placebo, analyzed through the histological evaluation of fibrosis using the Ishak scale, defined as a reduction in the fibrosis value of at least one point on this scale;Timepoint(s) of evaluation of this end point: Change from baseline biopsy in histological fibrosis score measured using the Ishak scale at 6,12,18 months. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Analyze the effect of simvastatin on liver fibrosis evaluated by non-invasive methods: to. Change in liver elasticity measured by transient liver elastography at 6, 12, and 18 months. b. Change in liver elasticity measured by ERM at 18 months. c. Changes in serum markers and liver fibrosis scores validated for ALD and widely used in the general population: FIB-4 (Fibrosis Index for Liver Fibrosis) and ELF (Enhanced liver Fibrosis), pro-collagen 3, hydroxyproline, metalloproteinase 1 and telopeptide, at 18 months. 2. Study the changes in liver fibrosis and other histological parameters of the disease: d. Changes in liver fibrosis assessed using the Metavir scale, the EPOS scale and the “7-tier fibrosis staging system for ALD” scale, at 18 months. and. Change in the “collagen proportional area” or area occupied by collagen in liver biopsies stained using psirious network and analyzed with Image J software, at 18 months. F. Changes in histological parameters of chronic alcoholic liver disease: steatosis, neutrophil infiltration, Mallory's hyaline, ballooning of hepatocytes, etc .; at 18 months. 3. Changes in the diversity and taxonomic composition of the intestinal microbiota by massive sequencing, at 18 months of treatment. 4. Analyze the markers of systemic inflammation, immune response, bacterial translocation and endothelial dysfunction: and. Change in levels of pro-inflammatory cytokines associated with alcoholic liver disease: IL-6, TNFa, and procalcitonin; at 18 months. F. Change in levels of bacterial translocation markers: bacterial lipopolysaccharide and lipopolysaccharide-bound protein; at 18 months. g. Change in levels of endothelial dysfunction markers: nitric oxide (NO), Von Willebrand factor (vWF); at 18 months. h. Change in the inflammatory profile of circulating immune cells: lymphocytes, monocytes and neutrophils; at 18 months. 5. analyse gen SLCO1B1 polimorfism and muscular toxicity 6.Incidence of adverse effects and safet | — |
Countries
Spain
Contacts
Public ContactAnna Cruceta
CTU(clinical Trial Unit)
Outcome results
None listed