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

Phase 3

Terminated

• Conditions: Alcoholic Cirrhosis; Iron Overload
• Interventions: Procedure: phlebotomy

• Registration Number: NCT01342705
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Brief Summary

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.

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 Timeline

• Study First Submitted: 2011-04-14
• Study First Submitted QC: 2011-04-26
• Study First Posted: 2011-04-27
• Study Start: 2011-05
• Status Verified: 2012-11
• Primary Completion: 2014-06
• Study Completion: 2014-06
• Last Update Submitted: 2015-04-20
• Last Update Posted: 2015-04-21

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 17

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
phlebotomy	phlebotomy	-

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (7)

Jean Verdier; 🇫🇷 Bondy, France

Avicenne; 🇫🇷 Bobigny, France

Amiens University Hospital : 🇫🇷 Amiens, France

CHU Bordeaux univerity hospital 1; 🇫🇷 Bordeaux, France

CHU Bordeaux University hospital 2; 🇫🇷 Bordeaux, France

CHU; 🇫🇷 Rouen, France

Antoine Béclère; 🇫🇷 Clamart, France