Primary Prevention Hepatocellular Carcinoma by Metformin
Primary Prevention Hepatocellular Carcinoma by Metformin
Metformin treatment during 36 months could be associated with decreased risk of HCC
 occurrence and liver related death in patients with compensated HCV cirrhosis and
 insulinoresistance.

 This study is an ancillary of the observational study from the CIRVIR cohort in which more
 than 1200 patients with compensated HCV cirrhosis are currently included.

 participating centers : 26
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:

 1. missing data for the primary efficacy endpoints

 2. no study drug received

 3. violation of inclusion criteria

 4. 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.
Inclusion Criteria:

 -  Age of 18 years or older

 -  Patients included in ANRS cohort CO12 CirVir

 -  Without Hepatic local lesion (s) suggestive of HCC in the inclusion

 -  No indication for liver transplantation at baseline

 -  Child Pugh A or B7 at inclusion

 -  Without co-infection with HIV or HBV

 -  No history of lactic acidosis or of lactic acidosis at inclusion

 -  Insulino-resistance: (HOMA ≥2), or Body mass index≥ 25 kg/m ² without diabetes, or
 untreated known diabetes with HbA1c < 7 %

 -  No treatment with Metformin or other oral hypoglycemic containing metformin within 30
 days before enrollment

 -  Available healthcare insurance

 -  Signed written informed consent.

 Exclusion Criteria:

 -  Patient under guardianship or homeless

 -  Pregnant or breast-feeding women

 -  Patients with severe disease (excluding HCV liver disease) may threaten short-term
 life

 -  Cirrhosis with Child Pugh score> 7

 -  An alcohol consumption, higher than 40g / day for men and 30g / day for women

 -  Type 1 diabetes

 -  Diabetes treated with metformin

 -  Diabetes not treated with metformin with HbA1c ≥ 7%

 -  Hypersensitivity / intolerance in biguanides

 -  Hypersensitivity to the active substance or to any of the excipients.

 -  Kidney failure defined by creatinine clearance less than 30 ml/ min (MDRD formula)