Phlebotomy and Risk of Hepatocellular Carcinoma in Patients With Compensated Alcoholic Cirrhosis (CIRROX)

Influence of Iron Depletion by Phlebotomy on the Risk of Hepatocellular Carcinoma Occurrence in Patients With Compensated Alcoholic Cirrhosis. Prospective, Multicentre, Randomized Trial

The main objective of the study is to assess in patients with compensated alcoholic cirrhosis and hepatic iron overload (HIO), as assessed by MRI, the effect of phlebotomy in order to lower and maintain serum ferritin below 50 µg / l on the risk of hepatocellular carcinoma (HCC) occurrence. The effect of bloodletting will be jointly evaluated on 1) episodes of hepatic decompensation, 2) non HCC liver-related mortality 3) changes in HIO during follow-up.

Study Overview

• Status: Terminated
• Conditions: Iron Overload; Alcoholic Cirrhosis
• Intervention / Treatment: Procedure: phlebotomy

Detailed Description

Purpose

The role of iron in liver carcinogenesis is supported by human, animal and cellular models through direct and indirect mechanisms. The accumulation of iron promotes liver cell proliferation and is responsible for direct structural damage or mutations of DNA caused by free iron itself or reactive oxygen species generated by its accumulation in the liver.

The influence of hepatic iron overload (HIO) on the risk of hepatocellular carcinoma (HCC) is well established in patients with genetic hemochromatosis or HCC developed on non-cirrhotic liver. However, the influence of HIO on the risk of occurrence of HCC in other chronic liver disease (including alcoholic and viral C) has been controversial. Recently, a prospective study including a large population of patients with cirrhosis (n = 301) classified according to the aetiology of liver disease (alcohol, n = 162 or hepatitis C virus (HCV)infection, n = 139) has shown the association between HIO and the occurrence of HCC in patients with alcoholic cirrhosis. Thus, the assessment of liver iron in routine clinical practice could allow the identification of patients at higher risk of developing HCC and in whom preventive measures such as iron depletion by phlebotomy could be undertaken. Based on the model of genetic hemochromatosis in which its effectiveness on survival improvement and even regression of hepatic injury has been shown, its effectiveness on the prognosis and prevention of HCC occurrence in patients with alcoholic cirrhosis must now be studied in prospective multicentre randomized trials.

The main objective of the study is to assess in patients with compensated alcoholic cirrhosis and HIO, as assessed by MRI, the effect of phlebotomy in order to lower and maintain serum ferritin below 50 µg / l on the risk of HCC occurrence. The effect of bloodletting will be jointly evaluated on 1) episodes of hepatic decompensation, 2) non HCC liver-related mortality 3) changes in HIO during follow-up.

Study Type: Interventional Study Design: Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Prevention

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Amiens, France
    • Amiens University Hospital :
  • Bobigny, France
    • Avicenne
  • Bondy, France, 93140
    • Jean Verdier
  • Bordeaux, France
    • CHU Bordeaux univerity hospital 1
  • Bordeaux, France
    • CHU Bordeaux University hospital 2
  • Caen, France
    • CHU
  • Clamart, France
    • Antoine Béclère
  • Grenoble, France
    • CHU
  • Lille, France
    • CHU
  • Montpellier, France
    • CHU
  • Nancy, France
    • CHU
  • Nice, France
    • CHU
  • Rennes, France
    • CHU
  • Rouen, France
    • CHU

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age over 18
• Biopsy-proven alcoholic cirrhosis
• No previous HCC (treated or not)
• Excessive alcohol consumption, defined by more than 21 glasses weekly in women and more than 28 glasses weekly in men for at least 10 years, and considered as the main cause for liver cirrhosis
• Signed written informed consent
• Hepatic iron overload assessed by MRI (Iron hepatic concentration ≥ 80 μmol/g)

Exclusion Criteria:

• Subjects deprived of their liberty by judicial or administrative decision
• Pregnant women
• Serious associated short-term life threatening disease (except HIV viral co-infection, or the liver disease itself)
• Impossibility of monitoring, whatever the reason.
• Contraindication of phlebotomy

• Haemoglobin <13.5 g/dL for men and <12.5g/dL for women (threshold established by the French Blood Agency)

  • Congestive heart failure or coronary heart disease
  • Hepatic failure (TP<60%), renal failure (GFR <50 ml/min) or respiratory insufficiency (chronic dyspnea)
  • Poor venous system
• Complication of cirrhosis at time of inclusion (defined as bleeding related to portal hypertension, encephalopathy or ascites)
• Presence of hepatitis B or hepatitis C co-infection
• Presence of liver focal lesion suggestive of HCC
• Child-Pugh score greater than or equal to 7 (Class B or C) at time of inclusion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: control
Experimental: phlebotomy	Procedure: phlebotomy; Procedure: Phlebotomy of 4 ml / kg to obtain (1 phlebotomy every 14 days) and maintain (1 phlebotomy every 3 months) a serum ferritin below 50 µg / l.; Other Names: Bloodletting; Iron depletion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of HepatoCellular Carcinoma during follow-up	the cumulative incidence of HCC will be estimated considering death prior to the event of interest as competing risk outcomes	3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of hepatic decompensation episodes in study participants	3 years
Cumulative incidence of death non related to hepatoCellular Carcinoma	3 years
Number of Participants with Adverse Events as a Measure of Safety and Tolerability	3 years

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Pierre NAHON, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: April 14, 2011
• First Submitted That Met QC Criteria: April 26, 2011
• First Posted (Estimate): April 27, 2011

Study Record Updates

• Last Update Posted (Estimate): April 21, 2015
• Last Update Submitted That Met QC Criteria: April 20, 2015
• Last Verified: November 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Pathologic Processes; Metabolic Diseases; Alcohol-Related Disorders; Substance-Related Disorders; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Iron Metabolism Disorders; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Fibrosis; Carcinoma, Hepatocellular; Liver Cirrhosis; Iron Overload; Liver Cirrhosis, Alcoholic
• Other Study ID Numbers: P091107