Remedial Mechanism of Simvastatin and Ursodeoxycholic Acid in Liver Cirrhosis: Crosstalk of Bile Secretion, Gut Microbiome, and Host Immune Response

NCT07102979 | Terminated DMC

• 2 other identifiers: IRB 202201398A3CMRPG8P0291
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

This exploratory, randomized, open-label pilot study evaluated gut microbiota, fecal bile acid profiles, inflammatory markers, and fibrosis-related biomarkers in adults with chronic hepatitis B or hepatitis C after viral control. The study included a randomized cohort with advanced liver fibrosis and a non-randomized comparison cohort without advanced fibrosis. Viral control was defined as hepatitis B virus suppression during antiviral therapy or sustained virologic response after hepatitis C treatment. The main questions addressed by the study were: Do participants with advanced liver fibrosis differ from those without advanced fibrosis in their baseline gut microbiota, fecal bile acid profiles, inflammatory markers, or fibrosis-related biomarkers? What within-participant changes in these measures are observed after six months of treatment with ursodeoxycholic acid (UDCA), simvastatin, or combined UDCA plus simvastatin? What descriptive patterns of change are observed across the three active-treatment groups? Advanced liver fibrosis was operationally defined during enrollment as a FibroScan liver stiffness measurement of ≥9.5 kPa. Thirteen participants with presumed advanced liver fibrosis were randomized to observation without study medication, UDCA alone, simvastatin alone, or combined simvastatin plus UDCA. One randomized participant was subsequently excluded from the analysis after eligibility review because the advanced-fibrosis criteria were not confirmed, leaving 12 eligible randomized participants, with three participants in each study group. An additional six participants with non-advanced fibrosis, defined by a FibroScan liver stiffness measurement of \<6.0 kPa, were enrolled as a non-randomized baseline comparison group. Baseline blood and stool samples were collected from all 19 enrolled participants. The final baseline analysis set included 18 eligible participants: 12 participants with advanced fibrosis and six participants without advanced fibrosis. Follow-up blood and stool samples were collected after six months from the nine participants in the three active-treatment groups. The observation group and the non-advanced fibrosis comparison group contributed baseline data only and did not undergo post-treatment sampling. Recruitment was substantially slower than anticipated and was discontinued after the available study funding was exhausted. The study was therefore terminated before reaching its originally planned enrollment target. The final actual enrollment was 19 participants, of whom 18 were included in the final analysis set. Because only three participants were available in each randomized study group, all treatment-related analyses were considered exploratory and hypothesis-generating. The study was not designed or adequately powered to establish clinical efficacy, histological fibrosis regression, or superiority of combination therapy.

Conditions

Liver Fibrosis

Keywords

Advanced liver fibrosis; Fecal bile salt; UDCA; Statin

Outcome Measures

Primary Outcomes (2)

• Change in liver fibrosis biomarker (TGF-β1)

  Measurement of serum fibrosis-related marker TGF-β1. This will assess the antifibrotic effects of simvastatin, UDCA, and their combination in patients with stable liver cirrhosis.

  Baseline and 6 months after treatment initiation

• Change in liver fibrosis biomarker (Type IV collagen)

  Measurement of serum fibrosis-related marker Type IV collagen. This will assess the antifibrotic effects of simvastatin, UDCA, and their combination in patients with stable liver cirrhosis.

  Baseline and 6 months after treatment initiation

Secondary Outcomes (2)

• Change in Cirrhosis Dysbiosis Ratio (CDR)

  Baseline and 6 months after treatment

• Change in Serum Inflammatory Cytokines

  Baseline and 6 months after treatment

Study Arms (5)

Advanced liver fibrosis -Control Group

NO INTERVENTION

Participants receive standard clinical monitoring without any investigational treatment. No simvastatin or ursodeoxycholic acid (UDCA) is administered during the 6-month study period.

Advanced liver fibrosis -UDCA Group

EXPERIMENTAL

Participants receive ursodeoxycholic acid (UDCA) at a dose of 10 mg/kg/day orally for 6 months to evaluate its effect on liver fibrosis, bile acid metabolism, and gut microbiota.

Drug: Ursodeoxycholic Acid (URSO)

Advanced liver fibrosis -Simvastatin Group

EXPERIMENTAL

Participants receive simvastatin at a dose of 40 mg/day orally for 6 months. The treatment aims to assess effects on fibrosis markers, inflammation, and gut microbiota composition.

Drug: Simvastatin

Advanced liver fibrosis -Simvastatin + UDCA Group

EXPERIMENTAL

Participants receive a combination of simvastatin (40 mg/day) and ursodeoxycholic acid (UDCA) (10 mg/kg/day) orally for 6 months. The combination therapy is evaluated for potential synergistic effects on fibrosis reduction, bile acid modulation, and microbiota restoration.

Drug: Ursodeoxycholic Acid (URSO); Drug: Simvastatin

Non-advanced Fibrosis Comparison Cohort

NO INTERVENTION

Participants without advanced fibrosis were enrolled as a non-randomized cohort for baseline comparison. No study medication was administered.

Interventions

Ursodeoxycholic Acid (URSO) DRUG

Ursodeoxycholic acid (UDCA) was administered orally at a dose of 10 mg/kg/day for 6 months.

Advanced liver fibrosis -Simvastatin + UDCA Group; Advanced liver fibrosis -UDCA Group

Simvastatin DRUG

Simvastatin was administered orally at a dose of 40 mg/day for 6 months.

Advanced liver fibrosis -Simvastatin + UDCA Group; Advanced liver fibrosis -Simvastatin Group

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults aged 18 to 75 years
• Diagnosed with advanced fibrosis; the cohort was operationally defined by a FibroScan liver stiffness measurement of ≥9.5 kPa.
• Achieved sustained virological response (SVR) at least 6 months after hepatitis C treatment, or
• Non-replicating hepatitis B infection (undetectable viral load) for at least 6 months
• Able and willing to provide informed consent

You may not qualify if:

• Current or prior use of statins
• Liver decompensation (jaundice, ascites, hepatic coma, or esophagogastric varices)
• Diagnosed hepatocellular carcinoma or other liver cancers
• Alcoholic liver disease or moderate-to-severe fatty liver
• Diagnosed diabetes mellitus
• Chronic kidney disease
• Use of antibiotics within the past 3 months
• Use of gastric ulcer medications such as proton pump inhibitors (PPIs)
• Pregnancy or breastfeeding
• Any condition deemed by the investigator to interfere with study participation or outcomes

Sponsors & Collaborators

• Chang Gung Memorial Hospital: lead

Study Sites (1)

Kaohsiung Chang Gung Memorial Hospital

Kaohsiung City, Others, 833, Taiwan

Location

Related Publications (4)

• Islam KB, Fukiya S, Hagio M, Fujii N, Ishizuka S, Ooka T, Ogura Y, Hayashi T, Yokota A. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology. 2011 Nov;141(5):1773-81. doi: 10.1053/j.gastro.2011.07.046. Epub 2011 Aug 10.

  PMID: 21839040 RESULT

• Chen Y, Yang F, Lu H, Wang B, Chen Y, Lei D, Wang Y, Zhu B, Li L. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology. 2011 Aug;54(2):562-72. doi: 10.1002/hep.24423. Epub 2011 Jun 26.

  PMID: 21574172 RESULT

• Bajaj JS, Hylemon PB, Ridlon JM, Heuman DM, Daita K, White MB, Monteith P, Noble NA, Sikaroodi M, Gillevet PM. Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. Am J Physiol Gastrointest Liver Physiol. 2012 Sep 15;303(6):G675-85. doi: 10.1152/ajpgi.00152.2012. Epub 2012 Jul 19.

  PMID: 22821944 RESULT

• Bajaj JS, Ridlon JM, Hylemon PB, Thacker LR, Heuman DM, Smith S, Sikaroodi M, Gillevet PM. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol. 2012 Jan 1;302(1):G168-75. doi: 10.1152/ajpgi.00190.2011. Epub 2011 Sep 22.

  PMID: 21940902 RESULT

MeSH Terms

Conditions

Liver Cirrhosis

Interventions

Ursodeoxycholic Acid; Simvastatin

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Deoxycholic Acid; Cholic Acids; Bile Acids and Salts; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Cholanes; Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: This is an open-label study. No participants, investigators, or outcome assessors are masked to treatment allocation. All parties involved are aware of the assigned interventions.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a randomized, controlled, parallel-group study with four arms. Eligible participants with advanced liver fibrosis are randomly assigned in a 1:1:1:1 ratio to receive either (1) no treatment (control), (2) ursodeoxycholic acid (UDCA) alone, (3) simvastatin alone, or (4) a combination of simvastatin and UDCA for 6 months. Randomization is performed using block randomization to ensure balanced allocation across groups. The groups are followed in parallel, and no crossover occurs between arms. A separate healthy control group (non-cirrhotic) provides baseline microbiota and bile acid profile comparisons but is not included in the interventional randomization.

Study Record Dates

• First Submitted: July 29, 2025
• First Posted: August 5, 2025
• Study Start: January 1, 2024
• Primary Completion: December 22, 2025
• Study Completion: December 31, 2025
• Last Updated: August 6, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

TW (1)