SIMVASTATIN for Alcoholic liver disease | Chronic liver disease | Liver fibrosis

Inclusion criteria

• {"criterion_text":"- Age ≥ 18 years\n- Chronic alcohol-related liver disease according to international guidelines (EASL, European Association for the Study of the Liver) 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.\n- 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.\n- 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."}

Exclusion criteria

• {"criterion_text":"- Patients receiving statins or fibrates.\n- Patients with other etiologies of liver disease in addition to alcohol: hepatitis C, hepatitis B, autoimmune hepatitis, Wilson's disease, or hemochromatosis.\n- Patients in whom hepatitis C has been cured with antivirals in the 2 years prior to inclusion in the study.\n- Patients with a CK elevation of 50% or more above the upper limit of normal at the time of study inclusion\n- Gastrointestinal bleeding due to portal hypertension within the 12 months prior to inclusion in the study.\n- Clinical hepatic encephalopathy, defined as grade II-IV hepatic encephalopathy, in the 12 months prior to inclusion in the study.\n- Patients in need of diuretic treatment in the previous 6 months to control ascites or hydrothorax.\n- Spontaneous bacterial peritonitis within 12 months prior to study enrollment.\n- Patients with a Child-Pugh score > 8 points.\n- Hepatocellular carcinoma of any stage.\n- Patients with known muscle disease.\n- Patients with previous rhabdomyolysis.\n- Patients being treated with strong CYP3A4 enzyme inhibitors (see section 5.2: Concomitant drugs, not allowed and allowed).\n- Patients being treated with drugs with possible interactions with simvastatin (see section 5.2: Concomitant drugs, not allowed and allowed).\n- 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.\n- Patients with extrahepatic malignancies, including solid tumors and hematologic malignancies.\n- Patients with a history or an increased risk of intestinal obstruction.\n- Pregnancy or breastfeeding.\n- Patients included in other clinical trials during the previous month.\n- 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.\n- Presence of data on alcoholic hepatitis in liver biopsy upon inclusion.\n- Patients with contraindications for statins.\n- Known hypersensitivity to simvastatin.\n- Refusal to sign the informed consent."}

Primary endpoints

• {"endpoint_text":"- Change from baseline biopsy in the histological fibrosis score measured using the Ishak scale at 24 months.","definition_or_measurement_approach":"Histological evaluation of liver fibrosis using the Ishak scale on biopsy at baseline and at 24 months; main objective defines a significant reduction as a reduction in the fibrosis value of at least one point on the Ishak scale (proportion of patients with ≥1-point reduction)."}

Secondary endpoints

• {"endpoint_text":"- 1. Analyze the effect of simvastatin on liver fibrosis evaluated by noninvasive methods: a. Change in liver elasticity measured by transient liver elastography at 6, 12, 18 and 24 months. b. Change in liver elasticity measured by ERM at 24 months.","definition_or_measurement_approach":"Transient liver elastography measurements at 6, 12, 18 and 24 months; magnetic resonance elastography (ERM) at 24 months to assess change in liver elasticity."}
• {"endpoint_text":"- 1.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 6, 12, 18 y 24 months.","definition_or_measurement_approach":"Serial measurement of serum fibrosis markers and scores (FIB-4, ELF, procollagen 3, hydroxyproline, MMP-1, telopeptide) at 6, 12, 18 and 24 months."}
• {"endpoint_text":"- 2. Study the changes in liver fibrosis and other histological parameters of the disease: a. Absence of progression compared to the baseline biopsy in the histological fibrosis score measured using the Ishak scale at 24 months. b. Shift in the degree of liver fibrosis measured using the Ishak scale, estimated with ordinal analysis.","definition_or_measurement_approach":"Histological comparison of baseline and 24-month biopsies using Ishak scale to assess absence of progression and ordinal shifts in fibrosis grade."}
• {"endpoint_text":"- 2.c. Changes in liver fibrosis evaluated using the Metavir scale (including the shift evaluated with ordinal analysis), the EPOS scale, and the \"7-tier fibrosis staging system for ALD\" at 24 months. d. Change in the collagen proportional area in liver biopsies stained with Sirius red and analyzed with Image J software at 24 months. e. Changes in histological parameters of chronic alcoholic liver disease: steatosis, neutrophil infiltration, Mallory bodies, etc., at 24 months.","definition_or_measurement_approach":"Histological assessments at 24 months including Metavir, EPOS, 7-tier ALD staging, collagen proportional area via Sirius Red + ImageJ, and evaluation of histological features (steatosis, neutrophil infiltration, Mallory bodies)."}
• {"endpoint_text":"- 3. Changes in the diversity and taxonomic composition of the gut microbiota through massive sequencing, at 24 months of treatment.","definition_or_measurement_approach":"High-throughput sequencing of gut microbiota with analysis of diversity and taxonomic composition at 24 months."}
• {"endpoint_text":"- 4. Analyze the markers of systemic inflammation, immune response, bacterial translocation, and endothelial dysfunction: a. Change in the levels of pro-inflammatory cytokines associated with alcoholic liver disease: IL-6, TNFα, and procalcitonin; at 6, 12, 18, and 24 months. b. Change in the levels of bacterial translocation markers: bacterial lipopolysaccharide and lipopolysaccharide-binding protein; at 6, 12, 18, and 24 months.","definition_or_measurement_approach":"Serial measurement of inflammatory cytokines (IL-6, TNFα, procalcitonin) and bacterial translocation markers (LPS, LBP) at 6, 12, 18 and 24 months."}
• {"endpoint_text":"- 4.c. Change in the levels of endothelial dysfunction markers: nitric oxide (NO), von Willebrand factor (vWF); at 6, 12, 18, and 24 months. d. Change in the inflammatory profile of circulating immune cells: lymphocytes, monocytes, and neutrophils; at 24 months.","definition_or_measurement_approach":"Measurement of endothelial markers (NO, vWF) at 6, 12, 18, 24 months and inflammatory cell profiles (lymphocytes, monocytes, neutrophils) at 24 months."}
• {"endpoint_text":"- 5. Analyze the polymorphisms of the SLCO1B1 gene and their relationship with muscle toxicity.","definition_or_measurement_approach":"Genotyping for SLCO1B1 polymorphisms and correlation analysis with muscle adverse events/toxicity."}
• {"endpoint_text":"- 6. Incidence of adverse effects and safety of the treatment.","definition_or_measurement_approach":"Collection and reporting of adverse events and safety parameters throughout the study; incidence summarized up to 24 months."}

Spain

Earliest CTIS Part Ii Submission Date

03-12-2024

Latest Decision Or Authorization Date

11-12-2024

Processing Time Days

8

Number Of Sites

1

Number Of Participants

90

Primary sponsor

Full Name

Fundacio De Recerca Clinic Barcelona-Institut D’Investigacions Biomediques August Pi I Sunyer

Organisation Type

Laboratory/Research/Testing facility

Country Of Registered Address

Spain