Efficacy of the Combination of Simvastatin Plus Rifaximin in Patients With Decompensated Cirrhosis to Prevent ACLF Development

NCT03780673 | Completed Phase 2 DMC

• 1 other identifier: LIVERHOPE_EFFICACY
• Study Type: interventional
• Target: 254
• Locations: 7 countries
• Sites: 14

Brief Summary

The aim of this study is to assess the efficacy of oral administration of simvastatin plus rifaximin in patients with decompensated cirrhosis to halt the progression of the disease as assessed by prevention of the development of ACLF

Conditions

Liver Cirrhoses

Outcome Measures

Primary Outcomes (1)

• Incidence of ACLF at the end of the study

  Month 12

Secondary Outcomes (46)

• Time to transplant-free survival at months1, 3, 6, 9 and 12

  months 1, 3, 6, 9 and 12

• Severity of ACLF assessed by number and types of organ failures at baseline, 1 month, 3 months, 6 months, 9 months and 12 months

  months 1, 3, 6, 9 and 12

• Frequency of hospital admissions due to complications of cirrhosis assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months.

  baseline and months 1, 3, 6, 9 and 12

• Number of participants developing a new onset episode of ascitis assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months

  baseline and months 1, 3, 6, 9 and 12

• Number of participants presenting worsening of ascitis assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months

  baseline and months 1, 3, 6, 9 and 12

Study Arms (2)

Simvastatin 20 mg + Rifaximin 400 mg

EXPERIMENTAL

Simvastatin 20 mg/day and rifaximin 400 mg/8 hours orally for 12 months

Drug: Simvastatin; Drug: Rifaximin

Placebo of Simvastatin + Placebo of Rifaximin

PLACEBO COMPARATOR

Placebo of simvastatin and placebo of rifaximin orally for 12 months

Drug: Placebo of Simvastatin; Drug: Placebo of Rifaximin

Interventions

Simvastatin DRUG

Simvastatin 20 mg/day for 12 months

Simvastatin 20 mg + Rifaximin 400 mg

Rifaximin DRUG

Rifaximin 400/8 hours for 12 months

Simvastatin 20 mg + Rifaximin 400 mg

Placebo of Simvastatin DRUG

Placebo of Simvastatin once a day for 12 months

Placebo of Simvastatin + Placebo of Rifaximin

Placebo of Rifaximin DRUG

Placebo of Rifaximin/8 hours for 12 months

Placebo of Simvastatin + Placebo of Rifaximin

Eligibility Criteria

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

You may qualify if:

• Age ≥ 18 years old
• Cirrhosis defined by standard clinical criteria, ultrasonographic findings and/or histology
• Child-Pugh patients or Child-Pugh C patients (up to 12 points)

You may not qualify if:

• Patients with contraindications for statins or rifaximin therapy.
• Known hypersensitivity to simvastatin or rifaximin (or rifamycin derivatives).
• Patients on treatment with potent inhibitors of CYP3A4 enzyme
• Patients on treatment with drugs with potential interactions with simvastatin
• Patients with previous history of myopathy.
• Patients with previous history of intestinal obstruction or those who are at increased risk of this complication.
• Patients with ACLF according to the criteria published by Moreau et al.
• Serum creatinine ≥2 mg/dL (176.8 μmol/L).
• Serum bilirubin\>5 mg/dL (85.5 μmol/L).
• \. INR ≥2.5
• Current overt hepatic encephalopathy, defined as grade II-IV hepatic encephalopathy according to the New-Haven classification.
• 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.
• Patients on antiviral therapy for HCV or those who have received it within the last 6 months.
• Severe alcoholic hepatitis requiring corticosteroid therapy (Maddrey's Discriminant function ≥ 32 and/or ABIC score \> 6.7).
• Patients with active alcohol consumption of more than 21 units per week.

Sponsors & Collaborators

• Judit Pich: lead

Study Sites (14)

University Hospitals Leuven

Leuven, Belgium

Location

Beajuon Hospital

Clichy, Paris, 92110, France

Location

Universitatsklinikum Frankurt

Frankfurt, 60590, Germany

Location

Bologna University Hospital

Bologna, Italy

Location

Padova University Hospital

Padua, 35128, Italy

Location

San Giovanni Battista Hospital

Torino, 10129, Italy

Location

Academic Medical Centre

Amsterdam, 1105 AZ, Netherlands

Location

Hospital Clínic de Barcelona

Barcelona, España, 08036, Spain

Location

Hospital Universitari Vall d'Hebrón

Barcelona, 08035, Spain

Location

Hospital de Sant Pau

Barcelona, Spain

Location

Hospital Moisés Broggi

Barcelona, Spain

Location

Hospital Parc Taulí

Barcelona, Spain

Location

Hospital Gregorio Marañón

Madrid, Spain

Location

Royal Free Hospital

London, NW3 2QG, United Kingdom

Location

Related Publications (2)

• Pose E, Jimenez C, Zaccherini G, Campion D, Piano S, Uschner FE, de Wit K, Roux O, Gananandan K, Laleman W, Sole C, Alonso S, Cuyas B, Ariza X, Juanola A, Ma AT, Napoleone L, Gratacos-Gines J, Tonon M, Pompili E, Sanchez-Delgado J, Allegretti AS, Morales-Ruiz M, Carol M, Perez-Guasch M, Fabrellas N, Pich J, Martell C, Joyera M, Domenech G, Rios J, Torres F, Serra-Burriel M, Hernaez R, Sola E, Graupera I, Watson H, Soriano G, Banares R, Mookerjee RP, Francoz C, Beuers U, Trebicka J, Angeli P, Alessandria C, Caraceni P, Vargas VM, Abraldes JG, Kamath PS, Gines P; LIVERHOPE Consortium. Simvastatin and Rifaximin in Decompensated Cirrhosis: A Randomized Clinical Trial. JAMA. 2025 Mar 11;333(10):864-874. doi: 10.1001/jama.2024.27441.

  PMID: 39908052 DERIVED

• Marrache MK, Rockey DC. Statins for treatment of chronic liver disease. Curr Opin Gastroenterol. 2021 May 1;37(3):200-207. doi: 10.1097/MOG.0000000000000716.

  PMID: 33654016 DERIVED

MeSH Terms

Interventions

Simvastatin; Rifaximin

Intervention Hierarchy (Ancestors)

Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds

Study Officials

• Pere Ginès, MD

  Hospital Clinic of Barcelona

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Neither the participants nor the researchers will know which group the participants has been allocated to
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Clinical Research Manager. CTU Clinic

Model Details: Phase III, multicentre, double-blind placebo-controlled, randomized clinical trial

Study Record Dates

• First Submitted: November 29, 2018
• First Posted: December 19, 2018
• Study Start: January 3, 2019
• Primary Completion: December 1, 2022
• Study Completion: December 1, 2022
• Last Updated: May 24, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1); DE (1); ES (6); GB (1); BE (1); IT (3); NL (1)