Simvastatin Plus Rifaximin in Decompensated Cirrhosis (LIVERHOPE)

Judit Pich

Status and phase: Completed; Phase 2

Conditions: Cirrhoses, Liver

Treatments: Drug: Rifaximin 400 mg; Drug: Simvastatin 20 mg; Other: Placebo of Rifaximin; Other: Placebo of Simvastatin; Drug: Simvastatin 40mg

Study type: Interventional

Funder types: Other

Identifiers

NCT03150459

2016-004499-23 (EudraCT Number)

LIVERHOPE_SAFETY

Details and patient eligibility

About

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.

Full 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.

Enrollment: 44 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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44 participants in 3 patient groups, including a placebo group

Simvastatin 20 mg + Rifaximin 400 mg (group 1)

Experimental group

Description:

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

Treatment:

Drug: Simvastatin 20 mg

Drug: Rifaximin 400 mg

Simvastatin 40 mg + Rifaximin 400 mg (group 2)

Experimental group

Description:

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

Treatment:

Drug: Simvastatin 40mg

Drug: Rifaximin 400 mg

Placebo of Simvastatin + Placebo of Rifaximin (group 3)

Placebo Comparator group

Description:

Placebo simvastatin and placebo rifaximin orally for 12 weeks

Treatment:

Other: Placebo of Simvastatin

Other: Placebo of Rifaximin