Primary Prevention Hepatocellular Carcinoma by Metformin (METFOVIR)

January 10, 2017 updated by: Assistance Publique - Hôpitaux de Paris

PRIMARY PREVENTION OF HEPATOCELLULAR CARCINOMA BY METFORMIN IN PATIENTS WITH VIRAL C CIRRHOSIS : PROSPECTIVE MULTICENTER STUDY, RANDOMIZED CONTROL TRIAL. Ancillary Study of the ANRS CO12 CirVir Cohort

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

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

11

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Bobigny, France, 93009
        • Roulot Dominique

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 77 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Metformin

1000 mg (2x500 mg) at morning and 1000 mg (2x500 mg) at afternoon (2000 mg per day)

Metformin daily during 36 months
Drug: Metformin

1000 mg (2x500 mg) at morning and 1000 mg (2x500 mg) at afternoon (2000 mg per day)

Metformin daily during 36 months

Other Names:
  • Glucophage
Placebo Comparator: placebo tablet
2 tablets at morning and 2 tablets at afternoon 4 tablets per day
Drug: placebo tablet
4 tablets per day for 36 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
rate of HCC occurrence and liver related-death or transplantation.
Time Frame: at 6 months
at 6 months

Secondary Outcome Measures

Outcome Measure
Time Frame
occurrence of liver-related complications (Ascites , gastrointestinal bleeding, encephalopathy)
Time Frame: at 6 months
at 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

ANRS, Emerging Infectious Diseases

Investigators

  • Principal Investigator: Dominique Roulot, MD, Hospital AVICENNE

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2015

Primary Completion (Actual)

April 1, 2016

Study Completion (Actual)

April 1, 2016

Study Registration Dates

First Submitted

December 13, 2014

First Submitted That Met QC Criteria

December 17, 2014

First Posted (Estimate)

December 18, 2014

Study Record Updates

Last Update Posted (Estimate)

January 11, 2017

Last Update Submitted That Met QC Criteria

January 10, 2017

Last Verified

January 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • P120138

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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