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

Phase 3
18 Years
Not Enrolling
Alcoholic Cirrhosis, Iron Overload

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Trial Information

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


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:

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

Type of Study:


Study Design:

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

Outcome Measure:

Cumulative incidence of HepatoCellular Carcinoma during follow-up

Outcome Description:

the cumulative incidence of HCC will be estimated considering death prior to the event of interest as competing risk outcomes

Outcome Time Frame:

3 years

Safety Issue:


Principal Investigator

Pierre NAHON, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Assistance Publique - Hôpitaux de Paris


France: Ministry of Health

Study ID:




Start Date:

May 2011

Completion Date:

June 2017

Related Keywords:

  • Alcoholic Cirrhosis
  • Iron Overload
  • Carcinoma
  • Liver Cirrhosis
  • Fibrosis
  • Liver Cirrhosis, Alcoholic
  • Iron Overload
  • Carcinoma, Hepatocellular