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

Assistance Publique - Hôpitaux de Paris

Status and phase

Terminated

Phase 3

Conditions

Alcoholic Cirrhosis

Iron Overload

Treatments

Procedure: phlebotomy

Study type

Interventional

Funder types

Other

Identifiers

NCT01342705

P091107

Details and patient eligibility

About

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.

Full 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

Enrollment

17 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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