Clinical trial NCT03150459: Simvastatin Plus Rifaximin in Decompensated Cirrhosis
Official title: Safety and Tolerability of the Combination of Simvastatin Plus Rifaximin in Patients With Decompensated Cirrhosis: a Multicenter, Double-blind, Placebo Controlled Randomized Clinical Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cirrhoses, Liver
Lead sponsor: Institut d'Investigacions Biomèdiques August Pi i Sunyer
Sponsor class: OTHER
First posted: 2017-05-12
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase II, multicenter, double-blind placebo controlled, randomized clinical trial
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change from baseline in transaminases during the treatment period, to evaluate treatment-related toxicity.
timeFrame: Week 12
measure: Change from baseline in alkaline phosphatase during the treatment period, to evaluate treatment-related toxicity.
timeFrame: Week 12
measure: Change from baseline in creatine kinase during the treatment period, to evaluate treatment-related toxicity.
timeFrame: Week 12
Secondary outcomes:
measure: Appearance of muscle toxicity at weeks 2, 4, 6, 8, 10 and 12 as defined using a specific statin-associated myopathy questionnaire
timeFrame: Weeks 2, 4, 6, 8, 10 and 12
measure: Changes from baseline in plasma renin concentration levels at weeks 2, 4, 8 and 12.
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline in serum aldosterone levels at weeks 2, 4, 8 and 12.
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline in plasma norepinephrine levels at weeks 2, 4, 8 and 12.
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline in plasma copeptin levels at weeks 2, 4, 8 and 12.
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline of plasma cytokine levels including, but not limited to, VCAM-1 and ICAM-1
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline of plasma cytokine levels including, but not limited to, VEGF-A
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline of plasma cytokine levels including, but not limited to, Fractalkine
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline of plasma cytokine levels including, but not limited to, MIP-1α
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline of plasma cytokine levels including, but not limited to, Eotaxin
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline of plasma cytokine levels including, but not limited to, IP-10
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline of plasma cytokine levels including, but not limited to, RANTES
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline of plasma cytokine levels including, but not limited to, GM-CSF
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline of plasma cytokine levels including, but not limited to, IL-1β, IL-2, IL-6 and IL-8
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline of plasma cytokine levels including, but not limited to, MCP-1
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline of plasma cytokine levels including, but not limited to, oxidized form of albumin
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline of plasma cytokine levels including, but not limited to, HNA2
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline in plasma biomarker FABP4 at weeks 2, 4, 8 and 12.
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline in plasma biomarker CD-163 at weeks 2, 4, 8 and 12.
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline in urine biomarker NGAL at weeks 2, 4, 8 and 12.
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline in urine biomarker IL-18 at weeks 2, 4, 8 and 12.
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline in urine biomarker MCP-1 at weeks 2, 4, 8 and 12.
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline in urine biomarker osteopontin at weeks 2, 4, 8 and 12.
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes from baseline in urine biomarker albumin at weeks 2, 4, 8 and 12.
timeFrame: Weeks 2, 4, 8 and 12
measure: Changes in blood levels of bacterial DNA or bacterial products at weeks 2, 4, 8 and 12.
timeFrame: Weeks 2, 4, 8 and 12
measure: Number of patients with genetic polymorphisms of statins membrane transporter OATPB1 in patients developing treatment-related toxicity (defined as the primary endpoint of the study).
timeFrame: Week 12
measure: Proportion of patients with treatment-related serious adverse events during the study period.
timeFrame: Week 12
Other outcomes:
Locations:
city: Clichy
country: France
facility: Beajuon Hospital
state: Paris
city: Bonn
country: Germany
facility: Universitatsklinikum Bonn
city: Bologna
country: Italy
facility: Bologna University Hospital
city: Padova
country: Italy
facility: Padova University Hospital
city: Torino
country: Italy
facility: San Giovanni Battista Hospital
city: Amsterdam
country: Netherlands
facility: Academic Medical Centre
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: London
country: United Kingdom
facility: Royal Free Hospital
Study officials:
affiliation: Hospital Clinic of Barcelona
name: Pere Ginès, MD
role: STUDY_CHAIR
References:
citation: 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.