Hepatocellular carcinoma (HCC) is currently the first cause of death of patients with
compensated HCV cirrhosis.Despite progresses,existing therapies are limited in their ability
to prevent recurrences. Even diagnosed at early stage, long-term prognosis remains poor due
to the high rate of recurrence after local treatments. Liver transplantation the only
long-term curative treatment is limited by advanced age, comorbidities or the shortage of the
graft It concerns less than 5 % of HCC patients . Therefore, the best approach to reduce
mortality remains the reduction of HCC incidence.
Abundant observational studies have related a relation between insulinoresistance occurrence
and outcome of many cancers. The level of IR assessed by the HOMA index have been recognized
as an independent predictive factor of HCC occurrence in patients with compensated viral C
cirrhosis. Metformin, a Type 2 diabetic treatment drug, inhibits hepatic gluconeogenesis and
increases the stimulation of the glucose uptake in muscle.
Independently of its' anti diabetic effects, Metformin is credited of anti tumoral, anti
oxidant, anti inflammatory, and anti angiogenic properties.
Amount epidemiological and experimental data have demonstrated the anti tumoral and
chemopreventive effect of metformin in certain cancers.
From our cohort of patients with compensated HCV cirrhosis and not treated by insulin, we
have observed that the level of IR assessed by the HOMA was a strong and independent risk
factor of HCC occurrence and liver related death. We have also observed in our cohort of
diabetic patients with compensated HCV cirrhosis, that treatment by Metformin was associated
with a decreased risk of HCC occurrence and liver related death.
HYPOTHESIS
Treatment with metformin could decreased the HCC occurrence and liver related death or
transplantation.
MAIN OBJECTIVE
Evaluation the impact of Metformin treatment on HCC occurrence and liver related death in
patients with compensated HCV cirrhosis and Insulinoresistance SECONDARY OBJECTIVE
Occurrence of decompensation of the cirrhosis (ascite, sepsis, encephalopathy,
haemorrhage)
Evaluation of the treatment tolerance
MAIN CRITERION JUDGMENT
Rate of HCC occurrence or liver related-death or transplantation.
SECONDARY CRITERION JUDGMENT
Occurrence of decompensation of the cirrhosis (ascite, sepsis, encephalopathy,
haemorrhage),
Tolerance
STUDY ASSESSMENTS
The patient of CIRVIR cohort meeting the inclusion criteria will be invited to participate to
this study.
During their next visit, the hepatologist, will give full verbal and written information
regarding the objective procedures of the study and the possible benefice and side effects of
the treatment. A write informed consent will be obtained from all patients who agree to
participate to the study.
The treatment period will begin following randomization. On day M0 baseline measurements will
be taken and recorded, and metformin administration will be begun. In order to optimize the
treatment tolerance, it will be suggested to the patients to take the pill during or at the
end of the lunch. During the first week, the posology of the placebo and metformin will be
500 mg at the breakfast. After, the posology will be increased every week as follow: 500 mg
morning and afternoon, then 1000 mg morning and afternoon (2000 mg per day). In case of
intolerance, the maximum posology tolerated will be maintained. In fact regarding the primary
data of the trial regarding the effect of metformin on colonic polyp, it seems possible that
low dose of metformin are potentially active This treatment will continue until the end of
the study.
FOLLOW UP
Patients will be seen at one month and followed every 3 months. Clinical evaluation and HCC
screening are planed In CIRVIR cohort study, Every 6 months.
Duration of Treatment per patient:
• 36 months
Duration of Trial Recruitment:
• 24 months
PARTICIPATING CENTERS : 26
NUMBER OF SUBJECT
In order to demonstrate a reduction of 40% (HR 0.6) of events under metformin vs placebo with
80% power and 5% two-sided alpha risk, 200 patients per arm are necessary.A sample size
reassessment will be made after 50% and 75% of patients included based on predictive power
calculation.
We estimated that 5% of patients will not tolerate the treatment in the first month, and that
5% more will be lost to follow or not compliant to treatment during the follow up period.
Therefore, the number of patients to be included is 222 patients per group.
STATISTICAL ANALYSIS
Clinical data of all the patients will be prospectively collected in a computerized database
Populations analyzed The main analysis will be based on the intent-to-treat population (ITT)
of all randomized patients
In addition an explanatory analysis (PP) of all patients randomized & treated without major
protocol violations/deviations will be carried out. Pre-defined major protocol
violations/deviations are:
missing data for the primary efficacy endpoints
no study drug received
violation of inclusion criteria
Additional protocol violations will be possibly defined during the blind data review
Statistical tests. Main criterion: rate of HCC occurrence and liver related-death or
transplantation.
The cumulative incidence of HCC and liver-related death or transplantation will be compared
according to metformin treatment at inclusion using the log-rank test.
In addition, univariate Cox regression models will be used to identify predictive factors of
primary endpoint.
For each endpoint, variables with a P value less than 0.10 in the univariate analysis
predicting outcomes will be entered into stepwise Cox regression multivariate models. For
sensitivity analyses, the incidence of HCC will be also adjusted on usual risk factors. The
same models considering competing risks will be tested using the Fine and Gray test.
Secondary criteria : Occurrence of decompensation of the cirrhosis (ascite, sepsis,
encephalopathy, haemorrhage).
Comparisons between groups will be performed first in a univariate manner using the χ2 test
or the Fisher-exact tests. Multiple logistic regression models will be used to assessed a
possible difference between groups when adjusted on parameters known or identified during the
study as possibly affecting these outcomes.