Clinical trial NCT03780673: Efficacy of the Combination of Simvastatin Plus Rifaximin in Patients With Decompensated Cirrhosis to Prevent ACLF Development
Official title: Efficacy of the Combination of Simvastatin Plus Rifaximin in Patients With Decompensated Cirrhosis to Prevent ACLF Development: a Multicenter, Double-blind, Placebo Controlled Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Liver Cirrhoses
Lead sponsor: Institut d'Investigacions Biomèdiques August Pi i Sunyer
Sponsor class: OTHER
First posted: 2018-12-19
Enrollment: 254
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase III, multicentre, double-blind placebo-controlled, randomized clinical trial
Primary purpose: TREATMENT

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

Detailed 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to a concern of potential higher liver and muscle toxicity in this population, a first LIVERHOPE_SAFETY clinical trial (unpublished) was undergone to assess safety and toxicity of statins with decompensated cirrhosis.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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of ACLF at the end of the study
timeFrame: Month 12
Secondary outcomes:
measure: Time to transplant-free survival at months1, 3, 6, 9 and 12
timeFrame: months 1, 3, 6, 9 and 12
measure: Severity of ACLF assessed by number and types of organ failures at baseline, 1 month, 3 months, 6 months, 9 months and 12 months
timeFrame: months 1, 3, 6, 9 and 12
measure: Frequency of hospital admissions due to complications of cirrhosis assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months.
timeFrame: baseline and months 1, 3, 6, 9 and 12
measure: Number of participants developing a new onset episode of ascitis assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months
timeFrame: baseline and months 1, 3, 6, 9 and 12
measure: Number of participants presenting worsening of ascitis assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months
timeFrame: baseline and months 1, 3, 6, 9 and 12
measure: Percentage of participants developing episodes of renal function impairment assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months
timeFrame: baseline and months 1, 3, 6, 9 and 12
measure: Percentage of participants developing the first episode of bleeding by esophageal or gastric varices at baseline, 1 month, 3 months, 6 months, 9 months and 12 months
timeFrame: baseline and months 1, 3, 6, 9 and 12
measure: Number of bleeding episodes by esophageal or gastric varices per patient assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months
timeFrame: baseline and months 1, 3, 6, 9 and 12
measure: Number of participants developing a new onset episode of hepatic encephalopathy (HE) assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months
timeFrame: baseline and months 1, 3, 6, 9 and 12
measure: Number of participants developing a new onset episode of bacterial infection assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months
timeFrame: baseline and months 1, 3, 6, 9 and 12
measure: Changes from baseline in plasma cytokine levels including, but not limited to, TNFα at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in plasma cytokine levels including, but not limited to, IL-6, IL-8, IL-10 and IL-1β at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in plasma cytokine levels including, but not limited to, IFN-ɣ at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in plasma cytokine levels including, but not limited to, G-CSF at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in plasma cytokine levels including, but not limited to, VCAM at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in plasma cytokine levels including, but not limited to, VCAM and VEGF at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in plasma cytokine levels including, but not limited to, oxide form of albumin at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in plasma cytokine levels including, but not limited to, HNA2 at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in plasma cytokine levels including, but not limited to, ADMA and SDMA at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in plasma biomarker FABP4 at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in plasma biomarker sCD-163 at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in plasma biomarker vWF at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in urine biomarker NGAL at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in urine biomarker MCP-1 at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in urine biomarker albumin at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in plasma renin concentration at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in plasma norepinephrine concentration at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in plasma copeptin concentration at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes from baseline in blood levels of bacterial DNA or bacterial products at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 12
measure: Changes in microbiome composition by analysis of microbial genes and signature at baseline, 3 months, 6 months and 12 months
timeFrame: baseline and months 3, 6 and 12
measure: Changes from baseline in liver function evaluated by MELD (Model For End-Stage Liver Disease) score at 1 month, 3 months, 6 months, 9 months and 12 months
timeFrame: months 1, 3, 6, 9 and 12
measure: Changes from baseline in liver function evaluated by CLIF-AD (Chronic Liver Failure - Acute Decompensation) score at 1 month, 3 months, 6 months, 9 months and 12 months
timeFrame: months 1, 3, 6, 9 and 12
measure: Changes from baseline in liver function evaluated by Child Pugh Score at 1 month, 3 months, 6 months, 9 months and 12 months
timeFrame: months 1, 3, 6, 9 and 12
measure: Change in quality of life assessed by CLDQ questionnaire (Chronic Liver Disease Questionnaire) at baseline, 1 month, 3 months, 6 months, 9 months and 12 months
timeFrame: baseline and months 1, 3, 6, 9 and 12
measure: Change of frailty and functional status assessed by Liver Frailty Index questionnaire at baseline, 1 month, 3 months, 6 months, 9 months and 12 months
timeFrame: baseline and months 1, 3, 6, 9 and 12
measure: Change of minimal hepatic encephalopathy assessed by PHES questionnaire (Psychometric Hepatic Encephalopathy Score) at baseline, 1 month, 3 months, 6 months, 9 months and 12 months
timeFrame: baseline and months 1, 3, 6, 9 and 12
measure: Changes from baseline in stigmatization assessed by a specific questionnaire at 3 months, 6 months and 12 months
timeFrame: months 3, 6 and 9
measure: Change in appearance of muscle toxicity at baseline, 1 month, 3 months, 6 months, 9 months and 12 months as defined using a specific statin-associated myopathy questionnaire
timeFrame: baseline and months 1, 3, 6, 9 and 12
measure: Number of patients with genetic polymorphisms of statins membrane transporter OATPB1 in all patients included in the study
timeFrame: month 12
measure: Changes from baseline in transaminases at 1 month, 3 months, 6 months, 9 months ans 12 months
timeFrame: months 1, 3, 6, 9 and 12
measure: Changes from baseline in alkaline phosphatase at 1 month, 3 months, 6 months, 9 months ans 12 months
timeFrame: months 1, 3, 6, 9 and 12
measure: Changes from baseline in creatine kinase at 1 month, 3 months, 6 months, 9 months ans 12 months
timeFrame: months 1, 3, 6, 9 and 12
measure: Proportion of patients and severity of treatment-related adverse events during the study period
timeFrame: month 12
measure: Annualized incidence of ACLF during the study period
timeFrame: month 12
measure: Time to overall at the end of the study
timeFrame: month 12
measure: Time to disease related survival at the end of the study
timeFrame: month 12
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Clichy
country: France
facility: Beajuon Hospital
state: Paris
city: Frankfurt
country: Germany
facility: Universitatsklinikum Frankurt
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 Clínic de Barcelona
state: España
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón
city: Barcelona
country: Spain
facility: Hospital de Sant Pau
city: Barcelona
country: Spain
facility: Hospital Moisés Broggi
city: Barcelona
country: Spain
facility: Hospital Parc Taulí
city: Madrid
country: Spain
facility: Hospital Gregorio Marañón
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: 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.