Efficacy of the Combination of Simvastatin Plus Rifaximin in Patients With Decompensated Cirrhosis to Prevent ACLF Development (2018-001698-25)

Judit Pich

Status and phase: Completed; Phase 3; Phase 2

Conditions: Liver Cirrhoses

Treatments: Drug: Placebo of Simvastatin; Drug: Simvastatin; Drug: Rifaximin; Drug: Placebo of Rifaximin

Study type: Interventional

Funder types: Other

Identifiers

NCT03780673

LIVERHOPE_EFFICACY

Details and patient eligibility

About

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

Full description

The current study was aimed at assessing whether a treatment based on combination of rifaximin and simvastatin would be effective in patients with decompensated cirrhosis to prevent ACLF development Considering that statins have been scarcely investigated in patients with decompensated cirrhosis due to a concern of potential higher liver and muscle toxicity in this population, a first LIVERHOPE_SAFETY clinical trial (unpublished) was undergone to assess safety and toxicity of statins with decompensated cirrhosis.

As a preliminary result of the LIVERHOPE_SAFETY clinical trial, it was concluded that the dose of Simvastatin 20mg per day plus Rifaximin is not associated to a higher risk of liver or muscle toxicity in patients with decompensated cirrhosis and simvastatin 20 mg was established for the LIVERHOPE_EFFICACY study.

Enrollment: 254 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 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)
• Women of child-bearing potential must have a negative pregnancy test in serum before the inclusion in the study and agree to use highly effective contraceptive methods during the study. Highly effective contraceptive methods will include: intrauterine device, bilateral tubal occlusion, vasectomized partner and sexual abstinence.

Exclusion criteria

• Patients on treatment with statins or rifaximin up to one month before study inclusion.
• Patients with contraindications for statins or rifaximin therapy.
• Known hypersensitivity to simvastatin or rifaximin (or rifamycin derivatives).
• Patients with CK elevation of 50% or more above the upper limit of normal at study inclusion.
• 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).
• 12. INR ≥2.5
• Bacterial infection within 10 days before study inclusion.
• Gastrointestinal bleeding within 10 days before study inclusion.
• 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.
• HIV infection.
• Patients with a history of significant extra hepatic 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 extra hepatic malignancies including solid tumours and hematologic disorders.
• Pregnancy or breastfeeding.
• Patients included in other clinical trials in the month before inclusion.
• 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.
• Refusal to give informed consent.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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254 participants in 2 patient groups, including a placebo group

Simvastatin 20 mg + Rifaximin 400 mg

Experimental group

Description:

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

Treatment:

Drug: Simvastatin

Drug: Rifaximin

Placebo of Simvastatin + Placebo of Rifaximin

Placebo Comparator group

Description:

Placebo of simvastatin and placebo of rifaximin orally for 12 months

Treatment:

Drug: Placebo of Simvastatin

Drug: Placebo of Rifaximin