Simvastatin Plus Rifaximin in Decompensated Cirrhosis

NCT ID: NCT03150459

Last Updated: 2019-03-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 44 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-07-26
• Study Completion Date: 2018-03-12

Brief Summary

The main purpose of this study is to investigate whether the combination of two different drugs, simvastatin and rifaximin, is safe in the treatment of patients with decompensated cirrhosis.

The secondary purpose is to see if this combination results in an improvement in inflammation markers in patients with cirrhosis and in an improvement in analytic parameters of progression of liver disease.

Detailed Description

Cirrhosis is the final stage of liver diseases, and currently, there is no effective treatment, with liver transplantation being the only curative solution in selected patients. As the number of donor organs for liver transplantation is limited and criteria for transplantation are strict, the current management of cirrhosis consists of treating its complications.

However, there is no effective therapy that prevents or cures the disease itself.

Rifaximin is an antibiotic that acts in the gastrointestinal tract. It is poorly absorbed to the general circulation and has low toxicity and good tolerability. Itis currently approved for use in patients with cirrhosis to prevent recurrent hepatic encephalopathy. Rifaximin decreases the transit of bacteria and bacterial products from the gut to the general circulation, preventing the chronic inflammation that takes place in cirrhotic patients.

Recent investigations have shown that simvastatin, a drug which is widely used to treat high cholesterol levels for the prevention of cardiovascular diseases, may have beneficial effects in patients with cirrhosis by preventing the progression of the disease and its complications. Although in the past decades there was a concern about its use in patients with liver disease due to its rare adverse effects (liver and muscle toxicity), recent clinical trials have shown that it can be safely used in patients with cirrhosis.

LIVERHOPE_SAFETY clinical trial have been designed to investigate whether the combination of these two drugs is safe in patients with cirrhosis, and also if it has potential beneficial effects in decreasing inflammation and improving analytical markers of progression of liver disease.

Conditions

Cirrhoses, Liver

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Simvastatin 20 mg + Rifaximin 400 mg (group 1)

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

Group Type: EXPERIMENTAL

Simvastatin 20 mg

Intervention Type: DRUG

Simvastatin 20 mg/day for 12 weeks (Group 1)

Rifaximin 400 mg

Intervention Type: DRUG

Rifaximin 400 mg/8 hours for 12 weeks (Group 1 and 2)

Simvastatin 40 mg + Rifaximin 400 mg (group 2)

Simvastatin 40 mg/day and rifaximin 400 mg/8 hours orally for 12 weeks

Group Type: EXPERIMENTAL

Simvastatin 40mg

Intervention Type: DRUG

Simvastatin 40 mg/day for 12 weeks (Group 2)

Rifaximin 400 mg

Intervention Type: DRUG

Rifaximin 400 mg/8 hours for 12 weeks (Group 1 and 2)

Placebo of Simvastatin + Placebo of Rifaximin (group 3)

Placebo simvastatin and placebo rifaximin orally for 12 weeks

Group Type: PLACEBO_COMPARATOR

Placebo of Simvastatin

Intervention Type: OTHER

Placebo of Simvastatin for 12 weeks (Group 3)

Placebo of Rifaximin

Intervention Type: OTHER

Placebo of Rifaximin for 12 weeks (Group 3)

Interventions

Simvastatin 20 mg

Simvastatin 20 mg/day for 12 weeks (Group 1)

Intervention Type: DRUG

Simvastatin 40mg

Simvastatin 40 mg/day for 12 weeks (Group 2)

Intervention Type: DRUG

Rifaximin 400 mg

Rifaximin 400 mg/8 hours for 12 weeks (Group 1 and 2)

Intervention Type: DRUG

Placebo of Simvastatin

Placebo of Simvastatin for 12 weeks (Group 3)

Intervention Type: OTHER

Placebo of Rifaximin

Placebo of Rifaximin for 12 weeks (Group 3)

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Age ≥ 18 years old.
• 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.
• Child Pugh B/C patients (from 7 to 12 points).
• 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.

Exclusion Criteria

• Patients on treatment with statins or rifaximin one month before study inclusion.
• Patients on the waiting list for liver transplantation.
• Patients with acute-on-chronic liver failure according to the criteria published by Moreau et al.
• Serum creatinine ≥2 mg/dL.
• Serum bilirubin>5 mg/dL.
• INR ≥2.5.
• Patients with CK elevation of 50% or more above the upper limit of normal at study inclusion.
• Bacterial infection within 15 days before study inclusion.
• Gastrointestinal bleeding within 15 days before study inclusion.
• Current overt hepatic encephalopathy, defined as grade II-IV hepatic encephalopathy.
• HIV infection.
• Hepatocellular carcinoma outside Milan criteria, defined as a single nodule ≤5 cm or a maximum of 3 nodules with none >3 cm.
• Patients on antiviral therapy for HCV or those who have received it within the last 6 months.
• Patients with previous history of myopathy.
• Patients on treatment with potent inhibitors of CYP3A4 enzyme (See section 5.2: Concomitant, nonpermitted and permitted medication)
• Patients on treatment with drugs with potential interactions with simvastatin
• 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.
• Patients with current extrahepatic malignancies including solid tumours and hematologic disorders.
• Patients with previous history or increased risk of intestinal obstruction.
• Pregnancy or breastfeeding.
• Patients included in other clinical trials in the previous month.
• Patients with active alcohol consumption of more than 3 units per day.
• 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.
• Severe alcoholic hepatitis requiring corticosteroid therapy (Maddrey's Discriminant function ≥ 32 and/or ABIC score > 6.7).
• Refusal to give informed consent.
• Patients with contraindications for statins or rifaximin.
• Known hypersensitivity to rifaxamin (or rifamycin derivatives) or to simvastatin.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Judit Pich

OTHER

Sponsor Role: lead

Responsible Party

Judit Pich

Clinical Research Manager. CTU Clínic

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Pere Ginès, MD

Role: STUDY_CHAIR

Hospital Clinic of Barcelona

Locations

Beajuon Hospital

Clichy, Paris, France

Universitatsklinikum Bonn

Bonn, , Germany

Bologna University Hospital

Bologna, , Italy

Padova University Hospital

Padua, , Italy

San Giovanni Battista Hospital

Torino, , Italy

Academic Medical Centre

Amsterdam, , Netherlands

Hospital Universitari Vall d'Hebrón

Barcelona, , Spain

Hospital Clínic de Barcelona

Barcelona, , Spain

Royal Free Hospital

London, , United Kingdom

Countries

France; Germany; Italy; Netherlands; Spain; United Kingdom

References

Pose E, Napoleone L, Amin A, Campion D, Jimenez C, Piano S, Roux O, Uschner FE, de Wit K, Zaccherini G, Alessandria C, Angeli P, Bernardi M, Beuers U, Caraceni P, Durand F, Mookerjee RP, Trebicka J, Vargas V, Andrade RJ, Carol M, Pich J, Ferrero J, Domenech G, Llopis M, Torres F, Kamath PS, Abraldes JG, Sola E, Gines P. Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Gastroenterol Hepatol. 2020 Jan;5(1):31-41. doi: 10.1016/S2468-1253(19)30320-6. Epub 2019 Oct 10.

Reference Type: DERIVED

PMID: 31607677 (View on PubMed)

Other Identifiers

2016-004499-23

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

LIVERHOPE_SAFETY

Identifier Type: -

Identifier Source: org_study_id